tag:blogger.com,1999:blog-6146376483374589779Fri, 09 Dec 2016 14:25:08 +0000geneticsautismschizophreniaconnectivityevolutionGWASepilepsycommon variantsmutationrare mutationssynaesthesiatwinswiringintelligencesynesthesiaclinical geneticsdevelopmentdyslexiaheritabilitymutationsrare variantsGCTAanimal modelsgenetic architectureinnatenessneurodevelopmentperceptionrare disorderssexual orientationADHDagnosiacolorcolourcopy number variantscortexenvironmentepigeneticsintellectual disabilitymaterialismnatural selectionneurodevelopmental disordernoisepersonalitypsychiatric geneticspsychosisrobustnessselectionwhole-genome sequencingCNVsDTIaxon guidancebrain developmentcausationchancecomplexityconsciousnessde novodepressiondopaminedyscalculiaemergenceepidemiologyepistasiseugenicsfitnessfragile Xfree willgeneticgenetic diagnosisgenotype-phenotype mappinghippocampushomosexualityinheritancelateralitymousemusicneural circuitsneurogeneticsneuroimagingoptogeneticspredictionprosopagnosiaquantitative traitsregenerationretinascreeningsequencingstatisticsstem cellssynapse formationsynaptogenesistestosteronetherapiesvisual systemAlzheimer'sDSM-5DSM-VEEGHuntington'sLRRLRRTMParkinson'sSNPsTammettVBMWilliams syndromeX-Menactivityadaptationagencyamphetamineantidepressantsantisocial behaviourasymmetrybehaviorbehaviourbehavioural traitsbenefitsbipolarbloggingbook reviewbrainbullshitcadherinscausalitycell typescomicscommon disorderscomplex disordersconectivityconferencecongenital amusiacorpus callosumcortical areascreativitycross-wiringcryptic genetic variationdeterminismdevelopmental trajectoriesdimorphismecstasyepistaticexperiencefMRIface blindnessfalse positivesfamiliesfragilityggene expressiongenetic interactionsgenetic predictiongenetics autismgeniusgenome-wide association studieshallucinationshapmaphearing voiceshemisphereheritableheterogeneityheterotopiahub neuronsimagingimpulsivityindividual differencesinfantinformationlanguagelearningleucine-richlinkagemagnetic fieldmapsmeaningmental retardationmigrationmoralitymultisensory integrationmutant micemyelinnanoscienceneural networksneurexinneurobollocksneuroliginneuronal networksneuroscienceoffspringoxytocinpainphenotypeplasticitypolygenicprenatal effectsprosodypruningpsychiatricpurposerandomnessreadingreal geneticsreductionismrepulsionsavantschemasscicommself-controlself-organisingsemaphorinserotoninsexsexual preferencesmall-worldsmokingsocial networksoulspecificitystructural imagingtarget selectionthalamocorticalthalamustransplantationvariancevasopressinwhite matterWiring the Brainhow the brain wires itself up during development, how the end result can vary in different people and what happens when it goes wronghttp://www.wiringthebrain.com/noreply@blogger.com (Kevin Mitchell)Blogger99125tag:blogger.com,1999:blog-6146376483374589779.post-6042474748989796092Thu, 12 May 2016 10:07:00 +00002016-05-12T03:07:19.448-07:00common variantsepistasiseugenicsGCTAGWASheritabilityintelligencerare mutationsThe genetics of educational attainment<div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-520092929 1073786111 9 0 415 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; mso-themecolor:hyperlink; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> <br /><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">A recently <a href="http://www.nature.com/nature/journal/vaop/ncurrent/full/nature17671.html">announced paper</a> reports the results of an enormous <a href="https://en.wikipedia.org/wiki/Genome-wide_association_study">genome-wide association study</a> for educational attainment. The authors found 74 regions of the genome where there are common variants that show statistically significant association with this trait. Here are my thoughts on what this study found, what it didn’t find and what those positive and negative results might mean. </span></div><div class="separator" style="clear: both; text-align: center;"><a href="https://www.google.com/url?sa=i&amp;rct=j&amp;q=&amp;esrc=s&amp;source=images&amp;cd=&amp;ved=0ahUKEwiM2NuNo9TMAhVnK8AKHSPdAroQjRwIBw&amp;url=http%3A%2F%2Fberkeleycuts.org%2Fabout-us%2F&amp;bvm=bv.121658157,d.ZGg&amp;psig=AFQjCNF9QpiHhOG6TGJel8AsnuxQ0Joq4w&amp;ust=1463133476246679&amp;cad=rjt"><img alt="https://www.google.com/url?sa=i&amp;rct=j&amp;q=&amp;esrc=s&amp;source=images&amp;cd=&amp;ved=0ahUKEwiM2NuNo9TMAhVnK8AKHSPdAroQjRwIBw&amp;url=http%3A%2F%2Fberkeleycuts.org%2Fabout-us%2F&amp;bvm=bv.121658157,d.ZGg&amp;psig=AFQjCNF9QpiHhOG6TGJel8AsnuxQ0Joq4w&amp;ust=1463133476246679&amp;cad=rjt" border="0" height="181" src="https://3.bp.blogspot.com/-RBIYuFprhJg/VzRUG4rJr4I/AAAAAAAAAw4/-VKnrHKg35MYRRtFkqvI4uzjNUuSX-N2ACLcB/s400/Screen%2BShot%2B2016-05-12%2Bat%2B10.59.26%2BAM.png" width="400" /></a></div><br /> <div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">First, it was a huge effort by a lot of people who should be congratulated for working together to carry out this analysis on such a huge scale. It is an interesting question and a worthwhile effort, in my view.&nbsp;The trait they measure, time spent in education, is an important one and has been shown to be moderately heritable. One <a href="http://www.ncbi.nlm.nih.gov/pubmed/23722424">large study</a> estimated the heritability at ~40%, meaning of the variance in this trait, <i style="mso-bidi-font-style: normal;">in the sample studied</i>, around that much was found to be attributable to genetic differences between people. (For reasons I can’t figure out, the current study cites that paper, but gives a figure of “at least 20%” for the heritability). There is also strong evidence that “<i style="mso-bidi-font-style: normal;">Educational attainment </i></span><i style="mso-bidi-font-style: normal;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-theme-font: major-latin;">is moderately correlated with other heritable characteristics, including cognitive function and personality traits related to persistence and self-discipline.</span></i><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-theme-font: major-latin;">”</span><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;"> Understanding the genetics of these traits is highly interesting, if for no other reason than that it can help us understand some of the major differences in human experience. </span><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-theme-font: major-latin;"></span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">The authors of the current study have clearly found what look like some <b>real associations</b> between common genetic variants and educational attainment. First, they replicate quite well across their different samples. Second, the variants are in a highly non-random set of genes – they are enriched for genes expressed in the brain during fetal development and for genes that encode proteins involved in neurodevelopment processes like neuronal differentiation, cell migration and axonal guidance – all the processes that are involved in putting the brain together! So, we can conclude that differences in how the brain develops can have some effect on intelligence or other traits (like drive) that contribute to variation in educational attainment. Of course, that doesn't sound surprising really when you say it like that – no more than the finding that common variants in skeletal growth genes influence height. But it didn't have to turn out that way.&nbsp;</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">What is more interesting to me is what they <b>did not find</b>. The 74 variants they find have tiny individual effects on the trait (even by GWAS standards) and collectively explain only 3% of the genetic variance in the trait. Their study was certainly well enough powered to detect common variants with even vary small effect sizes – the fact that they did not find any more of them is therefore strong evidence that they do not exist. </span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">So, instead of focusing on the variants they did find, one might instead ask what is contributing the other 97% of the genetic variance in this trait?&nbsp;</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">There are a few possible explanations:</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">1. There may exist many, many more common DNA variants that contribute to variation in this trait across the population, but if this is true, each of these must have an even smaller effect than the SNPs they have already found (approaching negligible, in fact). It would take enormous samples to find more of them and, given the diminishing returns in terms of effect sizes, they would likely explain only a very small additional percentage of the variance, even if many of them are found. &nbsp;</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">(Note that methods like <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014363/">Genomic Complex Trait Analysis</a>have been used to try and estimate how much of the variance in educational attainment is tagged by common variants across the whole population, even though we may not yet be able to identify them. <a href="http://www.ncbi.nlm.nih.gov/pubmed/27046643">Davies et al</a> estimated this at 21%).<span style="mso-spacerun: yes;">&nbsp;&nbsp;</span></span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">For what it’s worth, I am <a href="http://www.wiringthebrain.com/2013/11/the-dark-arts-of-statistical-genomics.html">generally skeptical</a> that this method can produce precise estimates, given the tiny signals it relies on. I am even more skeptical of the interpretation of such results, which is based on the assumption that because common variants can be used to index genetic relatedness across a sample, that any association between this index and phenotypic relatedness must be caused by the actions of those common variants and that it can indicate how many common variants must be involved. In fact this method tells us nothing about the number or allelic frequency of the causal variants involved.) </span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">2. Their statistical methodology may have missed common variants that have effects only in specific combinations (rather than their individual effects simply being summed). This is a general potential problem with GWAS methodology. However, with a sample size like the one they have, even variants that do have such <a href="http://www.wiringthebrain.com/2013/07/no-gene-is-island.html">epistatic interactions</a> would still be likely to show some non-zero individual effect on average. See here for more on "<a href="http://www.wiringthebrain.com/2015/11/what-do-gwas-signals-mean.html">what GWAS signals mean</a>".&nbsp;</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">3. The most likely explanation to me is that the genetic variants that make by far the biggest contribution to this trait are not common across the population, but rare. It would, in fact, be astonishing if rare mutations did not make an important contribution to the traits underlying educational achievement, especially intelligence. Generally speaking, rare mutations have bigger effects than common ones, we all carry many rare mutations, and intelligence is exactly the kind of trait that may be affected by many of them, either individually or in aggregate. </span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">This has profound implications for how we think about the <a href="http://www.wiringthebrain.com/2012/07/genetics-of-stupidity.html">genetics of intelligence</a>. What it means is that maybe there are no genes "for intelligence" - that is, genetic differences that explain most of the variance in intelligence <i style="mso-bidi-font-style: normal;">across the whole population</i>. Instead, our intelligence may be affected much more by the unique profile of rare mutations that we each carry.&nbsp;</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">These could be mutations in genes like those found in this GWAS study – ones that directly control processes of neural development or other aspects of how the brain functions. But there also could be a more general effect of overall mutational load, which might reduce the robustness of the processes of neural development. Under this model, intelligence may be not so much a specific trait, reflecting some particular brain processes, but rather a general fitness indicator. We may think of intelligence like we think of “performance” of a car or an aircraft – as relying not just on specific components but also, maybe even more so, on how they are all put together.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">Note also that nonlinear epistatic interactions are highly likely between the rare variants we each carry – <a href="http://www.wiringthebrain.com/2013/05/the-new-eugenics-same-as-old-eugenics.html">see here</a> for more on that and why it places serious limits on how much we will ever be able to predict intelligence.</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">So, overall, I think one of the strongest conclusions from this study is the one they do not draw – that most of the genetic variation in this trait (the unaccounted for 97%!) is probably NOT due to common variation but most likely to the profile of rare mutations that we each carry.</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">Finally, given how easily and widely this kind of stuff is misinterpreted, and how readily people ascribe viewpoints to people discussing it that they do not actually hold, it may be wise to issue a few disclaimers:</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">- saying a trait is partly heritable is not the same as implying it is entirely genetically determined</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">- there are clearly also important sociocultural factors affecting educational attainment</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">- there may also be important interactions between genetics and sociocultural factors</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">- showing some genetic influences on a complex trait is not the same as "reducing it" to the actions of a few genes (we are interested here in how <i>variation</i> in genes leads to <i>variation</i> in the trait; not how a trait like human intelligence comes about in the first place)</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">- the findings described here will be of no practical use in screening people or predicting their academic success</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">&nbsp;</span></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2016/05/the-genetics-of-educational-attainment.htmlnoreply@blogger.com (Kevin Mitchell)8tag:blogger.com,1999:blog-6146376483374589779.post-2303965495417816368Tue, 10 May 2016 11:34:00 +00002016-05-10T04:39:53.792-07:00brain developmentface blindnessgeneticslearningmultisensory integrationsynaesthesiaSchema formation in synaesthesia<div dir="ltr" style="text-align: left;" trbidi="on"><div class="MsoHeader" style="text-align: left;"><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} @font-face {font-family:"Apple Casual"; panose-1:0 1 4 0 0 0 0 0 0 0; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-2147483613 0 0 0 1 0;} @font-face {font-family:"Apple Chancery"; panose-1:3 2 7 2 4 5 6 6 5 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-2147483545 3 0 0 499 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoHeader, li.MsoHeader, div.MsoHeader {mso-style-priority:99; mso-style-link:"Header Char"; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; tab-stops:center 3.0in right 6.0in; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoFooter, li.MsoFooter, div.MsoFooter {mso-style-priority:99; mso-style-link:"Footer Char"; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; tab-stops:center 3.0in right 6.0in; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; mso-themecolor:hyperlink; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} pre {mso-style-noshow:yes; mso-style-priority:99; mso-style-link:"HTML Preformatted Char"; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:Courier; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-bidi-font-family:Courier;} span.HeaderChar {mso-style-name:"Header Char"; mso-style-priority:99; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:Header;} span.FooterChar {mso-style-name:"Footer Char"; mso-style-priority:99; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:Footer;} span.HTMLPreformattedChar {mso-style-name:"HTML Preformatted Char"; mso-style-noshow:yes; mso-style-priority:99; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:"HTML Preformatted"; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; font-family:Courier; mso-ascii-font-family:Courier; mso-hansi-font-family:Courier; mso-bidi-font-family:Courier; mso-ansi-language:EN-US;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} /* List Definitions */ @list l0 {mso-list-id:1657564380; mso-list-type:hybrid; mso-list-template-ids:-2063989736 67698703 67698713 67698715 67698703 67698713 67698715 67698703 67698713 67698715;} @list l0:level1 {mso-level-tab-stop:.5in; mso-level-number-position:left; text-indent:-.25in;} @list l0:level2 {mso-level-number-format:alpha-lower; mso-level-tab-stop:1.0in; mso-level-number-position:left; text-indent:-.25in;} @list l0:level3 {mso-level-number-format:roman-lower; mso-level-tab-stop:1.5in; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level5 {mso-level-number-format:alpha-lower; mso-level-tab-stop:2.5in; mso-level-number-position:left; text-indent:-.25in;} @list l0:level6 {mso-level-number-format:roman-lower; mso-level-tab-stop:3.0in; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level8 {mso-level-number-format:alpha-lower; mso-level-tab-stop:4.0in; mso-level-number-position:left; text-indent:-.25in;} @list l0:level9 {mso-level-number-format:roman-lower; mso-level-tab-stop:4.5in; mso-level-number-position:right; text-indent:-9.0pt;} ol {margin-bottom:0in;} ul {margin-bottom:0in;} </style><a href="https://3.bp.blogspot.com/-Ibxtf7sFiyY/VzHCnYyl18I/AAAAAAAAAwc/suJSdyWQBIkzQbO-CtOtsZWA4NnribFOQCLcB/s1600/Screen%2BShot%2B2016-05-10%2Bat%2B12.13.24%2BPM.png" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img border="0" height="320" src="https://3.bp.blogspot.com/-Ibxtf7sFiyY/VzHCnYyl18I/AAAAAAAAAwc/suJSdyWQBIkzQbO-CtOtsZWA4NnribFOQCLcB/s320/Screen%2BShot%2B2016-05-10%2Bat%2B12.13.24%2BPM.png" width="234" /></a><span style="font-family: &quot;times&quot; , &quot;times new roman&quot; , serif;"><span style="font-size: x-small;"><span lang="EN-GB">The following is an extract (just the text, not the figures) from a paper I wrote for the <a href="https://books.google.ie/books?id=3RYOCQAAQBAJ&amp;dq=schema+formation+in+synaesthesia&amp;source=gbs_navlinks_s">proceedings</a> of the </span>V International Conference <i>Synesthesia: Science and Art</i>. Alcalà la Real de Jaén. España. 16–19th May 2015.&nbsp;</span></span></div><div class="MsoHeader" style="text-align: left;"><br /></div><div class="MsoHeader" style="text-align: left;"><span style="font-family: &quot;times&quot; , &quot;times new roman&quot; , serif;"><span style="font-size: x-small;">Many of the ideas were also developed in a paper with my colleague Fiona Newell, on <a href="http://www.ncbi.nlm.nih.gov/pubmed/26231979">Multisensory Integration and Cross-Modal Learning in Synaesthesia: a Unifying Model</a>.</span></span><style><!-- /* Font Definitions */ @font-face {font-family:Arial; panose-1:2 11 6 4 2 2 2 2 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536859905 -1073711037 9 0 511 0;} @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1107305727 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; mso-bidi-font-size:10.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-GB;} p.MsoHeader, li.MsoHeader, div.MsoHeader {mso-style-unhide:no; mso-style-link:"Header Char"; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; tab-stops:center 207.65pt right 415.3pt; font-size:12.0pt; mso-bidi-font-size:10.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-GB;} span.HeaderChar {mso-style-name:"Header Char"; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:Header; mso-ansi-font-size:12.0pt; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style></div><b><span style="font-family: &quot;times&quot; , &quot;times new roman&quot; , serif;"></span></b><br /><div class="MsoNormal"><br /><br /><br /><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Abstract</span></b></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Psychologists use the term “<a href="http://www.wiringthebrain.com/2012/09/the-grand-schema-things.html">schema</a>” to refer to the information or knowledge that makes up our concept of an object. It includes all the attributes that the object has, such as the shapes of a letter and the sounds it can make, the shape of a numeral and the value it represents, or the face of a person and their name and everything you know about them. In many cases, those attributes are represented across very different brain areas (such as those conveying visual or auditory information, for example). With experience, the representations of the different attributes of an object become linked together, in the mind, by repeated co-occurrence. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">At the level of the brain, this must involve some kind of strengthening of connections across areas of the cerebral cortex so that a pattern of activity in one area (say that induced by the sight of the letter “A”) reliably co-activates or primes a particular pattern of activity in another area (say the sounds of the letter “A”). The brain is wired to enable this kind of communication between different areas, so that these sorts of associations can be learned by repeated exposure to contingent stimuli, for example as we learn the alphabet or our numbers. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB"><a href="https://en.wikipedia.org/wiki/Synesthesia">Synaesthesia</a> is characterised by the incorporation of additional attributes into the schema of an object – ones not reflecting the characteristics of the object itself but some internal associations triggered by it. I propose a model to account for synaesthesia based on innate differences in wiring between cortical areas, which lead to additional percepts (such as colours) being triggered by an object during learning. These repeated patterns eventually result in stable synaesthetic associations, despite the lack of reinforcement from the external world. This model can account for the heritability of the condition and evidence of cortical hyperconnectivity, but also for the learned nature of many of the inducing stimuli and observed trends in letter-colour or word-taste pairings. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In this conceptual framework, a natural contrast emerges between synaesthesia, on the one hand, and a number of other conditions, collectively known as “<a href="https://en.wikipedia.org/wiki/Agnosia">agnosias</a>”, on the other. These include dyslexia and dyscalculia, <a href="http://www.wiringthebrain.com/2010/04/hello-stranger.html">face blindness</a>, tone deafness, colour agnosia and others. These conditions seem to reflect an inability to incorporate all the attributes of an object into a schema, resulting in a “<a href="http://www.scientificamerican.com/article/the-neuroscience-of-tone/">lack of knowledge</a>” of particular types of objects. There is evidence that these result from decreased connectivity between brain regions. It is hoped that the study of synaesthesia may also inform on the mechanisms underlying these less benign conditions.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Introduction</span></b></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Synaesthesia </span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria;">is often described as a cross-sensory phenomenon, where, for example, particular sounds (such as words or musical notes) will induce a secondary percept (such as a color or taste), which is specific for each stimulus </span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria;"><span style="mso-no-proof: yes;">(</span></span><span lang="EN-GB"><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_3" title="Bargary, 2008 #2248"><span style="color: windowtext; mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes; text-decoration: none; text-underline: none;">Bargary and Mitchell, 2008</span></a></span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">; </span><span lang="EN-GB"><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_32" title="Hubbard, 2005 #4004"><span style="color: windowtext; mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes; text-decoration: none; text-underline: none;">Hubbard and Ramachandran, 2005</span></a></span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">)</span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria;"></span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria;">.<span style="mso-spacerun: yes;">&nbsp; </span>While these florid types of synaesthesia involve very vivid perceptual experiences, the more common manifestation is associative </span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria;"><span style="mso-no-proof: yes;">(</span></span><span lang="EN-GB"><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_45" title="Simner, 2012 #2395"><span style="color: windowtext; mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes; text-decoration: none; text-underline: none;">Simner, 2012</span></a></span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">)</span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria;">.<span style="mso-spacerun: yes;">&nbsp; </span>These cases involve the certain knowledge that some object, such as a letter or number, has, in addition to its normal attributes (shape, sound, value, etc.), some extra traits associated with it, such as spatial position, color, texture, even gender and personality.<span style="mso-spacerun: yes;">&nbsp; </span>These associated characteristics are stable, idiosyncratic and have typically formed an intrinsic part of the person’s schema of that object for as long as they can remember.<span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">A recurrent question in relation to synaesthesia is whether it represents a truly distinct phenomenon, qualitatively different from typical perception, or reflects instead an amplification or exaggeration of normal processes of multisensory integration </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_23" title="Deroy, 2013 #4737"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Deroy and Spence, 2013b</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_50" title="Ward, 2006 #1233"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Ward et al., 2006</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. A related question concerns the extent to which particular synaesthetic associations arise arbitrarily through intrinsic neural mechanisms or are driven instead by experience and learning in ways that may be common to all people </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_53" title="Watson, 2014 #4741"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Watson et al., 2014</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Both these questions bear on what is arguably the central question in the field: why do some people develop synaesthesia while most do not? The answers to these questions thus determine fundamentally how we conceive of synaesthesia.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">On the one hand, synaesthesia represents a dichotomous phenotype – people are relatively easily categorised as synaesthetes or non-synaesthetes. Moreover, the condition is clearly genetic in origin, often running in families with a Mendelian pattern of inheritance (some members clearly having the condition, others clearly not) </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_2" title="Asher, 2009 #2308"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Asher et al., 2009</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_4" title="Barnett, 2008 #2249"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Barnett et al., 2008</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_5" title="Baron-Cohen, 1996 #471"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Baron-Cohen et al., 1996</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_27" title="Galton, 1883 #1524"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Galton, 1883</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_41" title="Rich, 2005 #1629"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Rich et al., 2005</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_51" title="Ward, 2005 #1231"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Ward and Simner, 2005</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. The primary answer to the question of why some people develop synaesthesia is therefore that they inherit a genetic variant that strongly predisposes to the condition. This argues for some intrinsic difference as a necessary starting point in explaining the condition and against a model where general processes are sufficient to explain it. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">On the other hand, a number of lines of evidence suggest that whatever is happening in synaesthesia, it relies on or at least interacts with processes of multisensory integration that are common across all people. These include both acute cross-sensory activation as well as longer-term cross-modal learning. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">First, there is strong evidence that most areas of what has been deemed unisensory cortex are in fact essentially multisensory, with extensive anatomical cross-connectivity and at least some modulatory inputs from other modalities providing credible substrates for cross-sensory interactions </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_28" title="Ghazanfar, 2006 #4727"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Ghazanfar and Schroeder, 2006</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_40" title="Qin, 2013 #4729"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Qin and Yu, 2013</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. The idea that such interactions may be always present but not always consciously accessible is reinforced by the activation of visual areas in blind or blindfolded people </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_7" title="Bavelier, 2002 #1080"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Bavelier and Neville, 2002</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB"> and by the phantasmagoric audiovisual synaesthetic experiences associated with certain hallucinogens, such as lysergic acid (LSD), psilocybin or mescaline </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_43" title="Schmid, 2014 #4730"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Schmid et al., 2014</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_48" title="Sinke, 2012 #4728"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Sinke et al., 2012</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Such experiences indicate that the barriers between the senses are certainly not as rigid as typical experience suggests.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">However, drug-induced synaesthetic experiences have quite a different phenomenology, tending to involve florid, detailed and complex visual experiences induced by sound, especially music </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_23" title="Deroy, 2013 #4737"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Deroy and Spence, 2013b</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_48" title="Sinke, 2012 #4728"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Sinke et al., 2012</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. By contrast, developmental synaesthesia is characterised by more stable and sedate cross-sensory pairings of particular stimuli with particular additional percepts or conceptual attributes. These tend to be quite simple in nature, involving perceptual primitives rather than complex forms. The relevance of drug-induced synaesthesia to the mechanisms underlying developmental forms thus remains unproven.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There is another line of evidence, however, which supports the idea that normal multisensory integration processes are involved in synaesthesia. In particular, these are processes involved in categorical perception, which integrate information about objects across sensory domains and generate conceptual and supramodal representations.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For any form of synaesthesia, the particular pairings that emerge between inducers and concurrents are idiosyncratic and tend to be dominated by apparent arbitrariness in any individual. However, by looking across many synaesthetes, it is possible to discern clear trends in such pairings, for example between particular letters and their synaesthetic colours. In English speakers, the letter B may be more commonly blue than other colours (perhaps 30% of the time) and the letter Y more commonly yellow (as high as 50% of the time) </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_4" title="Barnett, 2008 #2249"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Barnett et al., 2008</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_41" title="Rich, 2005 #1629"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Rich et al., 2005</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. It is even apparent that, for some synaesthetes, all of their colour-letter pairings are derived from experience with childhood toys, such as refrigerator magnets </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_54" title="Witthoft, 2006 #4760"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Witthoft and Winawer, 2006</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Similarly, for many synaesthetes with number forms, the numbers 1 to 12 are arranged in a circle like a clock face </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_27" title="Galton, 1883 #1524"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Galton, 1883</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Many word-taste pairings can also be explained by semantic associations, such as “Cincinnati” tasting of cinnamon and “Barbara” tasting of rhubarb </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_44" title="Simner, 2007 #1655"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Simner, 2007</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There are thus clear cultural and semantic influences on the particular pairings that emerge in developmental synaesthesia. Some theorists have argued that such trends demonstrate that synaesthesia is induced by learning and, even further, that the <i style="mso-bidi-font-style: normal;">purpose</i> of synaesthesia is to aid in learning the inducing categories </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_1" title="Asano, 2013 #4742"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Asano and Yokosawa, 2013</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_38" title="Mroczko-Wasowicz, 2014 #4754"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Mroczko-Wasowicz and Nikolic, 2014</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_52" title="Watson, 2012 #4758"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Watson et al., 2012</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_55" title="Yon, 2014 #4759"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Yon and Press, 2014</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">How can the idea that synaesthesia reflects innate, genetic differences be reconciled with models that suggest it is driven by learning? Here I develop a theoretical framework showing that these two models are quite compatible (previously sketched out in </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_37" title="Mitchell, 2013 #4770"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Mitchell, 2013</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">). I argue: (i) that the predisposition to develop synaesthesia at all is genetic and innate; (ii) that the particular form and the pairings that emerge are driven largely by idiosyncratic connectivity differences; but (iii) that because the processes through which such pairings consolidate over time involve normal mechanisms of multisensory learning and categorical perception, the outcome can also be influenced by experience. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Synaesthesia as an associative phenomenon</span></b></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Developmental synaesthesia can be present in diverse forms and experienced in qualitatively distinct ways. One important distinction is between synaesthetes who are “projectors” and those who are “associators”. For the former, the concurrent percept is actively and vividly perceived, either out in the world or “in the mind’s eye”, while for the latter it is merely conceptually activated in the way that saying the word “banana” activates the concept of yellow, possibly even prompting a visual image of the object in that colour, but is unlikely to induce a veridical percept of yellow out in the world. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There is another important phenomenological distinction between lower-level, truly cross-sensory synaesthesia, and higher-level, more conceptual forms. In the former, taking coloured hearing as an example, any sound may induce a visual percept, whether the person has ever heard it before or not. The same sound will tend to induce the same visual percept, but this does not seem to require prior experience.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For many associative forms, however, the synaesthetic associations arise only with a particular set of stimuli. Crucially, these are almost exclusively stimuli that are (i) categorical, and (ii) learned (often over-learned), such as letters, numbers, days of the week, months of the year, musical notes, words, etc. The emergence of these associative forms of synaesthesia must thus necessarily involve learning at some level, and indeed clearly interacts with normal processes through which the multisensory attributes of objects are learned. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Cross-modal learning and categorical perception</span></b></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.nature.com/neuro/journal/v5/n2/fig_tab/nn0202-90_F2.html" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://www.nature.com/neuro/journal/v5/n2/fig_tab/nn0202-90_F2.html" border="0" height="224" src="https://1.bp.blogspot.com/-qXjL7YEJE0M/VzHGNO035WI/AAAAAAAAAwo/qv8CQsgkrS8Qs19JEk2p4zNuLOI67OpVACLcB/s320/Screen%2BShot%2B2016-05-10%2Bat%2B12.29.35%2BPM.png" width="320" /></a><span lang="EN-GB">As we develop perceptual expertise, we come to categorise objects into types and to recognise particular instances as tokens of such types </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_9" title="Binder, 2011 #4761"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Binder and Desai, 2011</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_33" title="Kourtzi, 2011 #4750"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Kourtzi and Connor, 2011</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Moreover, for any particular object, we develop a conceptual framework that incorporates its many properties – a schema linking its various attributes. Thus, the concept of a banana includes its typical shape, colour, taste, and other semantic associations. While such representations incorporate attributes from multiple sensory domains, they are essentially conceptual and <a href="https://en.wiktionary.org/wiki/supramodal">supramodal</a>. There is good evidence that such supramodal representations involve activity in specific associative areas of the brain, located in anterior inferotemporal cortex (AIT), which can be thought of as “knowledge areas” </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_17" title="Chiou, 2014 #4746"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Chiou et al., 2014</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_33" title="Kourtzi, 2011 #4750"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Kourtzi and Connor, 2011</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Even for recent inventions like written alphabets, these areas tend to develop in the same positions across people </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_20" title="Dehaene, 2007 #1492"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Dehaene and Cohen, 2007</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. This suggests that the specialisation of cortical areas for particular classes of objects relies on an evolutionarily programmed pattern of connectivity that places them at a convergence point of multiple, parallel hierarchies, enabling them to integrate information across the relevant sensory modalities.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Such areas are differentially activated by tasks that tap into semantic knowledge and lesions or temporary inactivation of these areas can result in object agnosias </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_19" title="De Renzi, 2000 #2371"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">De Renzi, 2000</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB"> – the inability to access all the attributes of an object when the concept is activated </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_17" title="Chiou, 2014 #4746"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Chiou et al., 2014</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_33" title="Kourtzi, 2011 #4750"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Kourtzi and Connor, 2011</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_36" title="Mitchell, 2011 #3060"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Mitchell, 2011</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. For example, prosopagnosia, or face blindness, represents an inability to recognise people’s identity from their faces, though other aspects of face processing may remain intact. Similarly, colour agnosia refers to the inability to link characteristic colours into the schemas of objects, despite normal colour perception and discrimination. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Both these conditions can be caused by injuries to associative areas, but, intriguingly, both can also be innate and inherited </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_8" title="Behrmann, 2005 #2357"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Behrmann and Avidan, 2005</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_24" title="Duchaine, 2007 #2338"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Duchaine et al., 2007</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_39" title="Nijboer, 2007 #2404"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Nijboer et al., 2007</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_49" title="van Zandvoort, 2007 #2403"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">van Zandvoort et al., 2007</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. The fact that such conditions can be genetic highlights the fact that differences in brain wiring (either structural or functional) can impact, very selectively, on higher-order conceptual processes, presumably by altering the anatomical substrates through which perceptual information is processed </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_36" title="Mitchell, 2011 #3060"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Mitchell, 2011</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Indeed, structural and functional neuroimaging studies have highlighted reduced connectivity within extended networks of cortical areas in these conditions. By contrast, synaesthesia may be caused by hyperconnectivity, linking additional areas into the conceptual schemas of learned categories of objects </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_36" title="Mitchell, 2011 #3060"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Mitchell, 2011</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The processes by which such schemas emerge can be illustrated by considering how letters are learned. As children are learning to read they must learn to recognise and distinguish the various graphemes of the alphabet and also link them to the appropriate phonemes of their native language </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_11" title="Blomert, 2010 #4762"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Blomert and Froyen, 2010</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. In the visual domain, recognising graphemes requires, firstly, extraction of increasingly complex visual features across the hierarchy of areas in the ventral visual stream </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_34" title="Kravitz, 2013 #4763"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Kravitz et al., 2013</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Though it is a simplification, it is roughly true that each level in the visual hierarchy extracts more complex features by integrating inputs from multiple neurons at the level below, eventually enabling representation of shapes and objects across the visual field. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Areas that are higher still become specialised for processing specific types of visual information that correspond to various categories (letters, faces, objects, scenes). This kind of categorical perception enables the recognition of various instances of an object – different sizes, views or versions (such as of the letter “A” (<i style="mso-bidi-font-style: normal;">A</i><b style="mso-bidi-font-weight: normal;">, </b></span><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: &quot;apple casual&quot;;">A,</span><span lang="EN-GB"> </span></b><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: &quot;apple chancery&quot;;">A,</span></b><span lang="EN-GB"> a</span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Apple Chancery&quot;;">))</span><span lang="EN-GB"> – all of which can activate the representation of the concept of the object </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_34" title="Kravitz, 2013 #4763"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Kravitz et al., 2013</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Similar processes arise as children learn spoken language – they develop expertise in recognising the typical speech sounds of their native language, but become deficient in distinguishing between uncommonly used phonemes. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Neuronal networks in general can learn in the following fashion. Any given stimulus will activate a distinct subset of neurons across an area of cortex, which can be thought of, reasonably accurately, as a two-dimensional sheet of highly interconnected cells. Due to their coincident activation, the connections between these neurons will be slightly strengthened </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_30" title="Hebb, 1949 #4766"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Hebb, 1949</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. If a particular stimulus is seen over and over again, this subset of neurons will become a functional unit, primed to respond en masse to similar stimuli. (More realistically, the properties of the stimulus may be represented not by one static pattern but by the dynamic trajectory of firing patterns across some time period </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_18" title="Daelli, 2010 #4747"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Daelli and Treves, 2010</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">).</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The patterns of neuronal activity that represent any one object can be thought of as attractor states – any stimulus that occupies a nearby spot in perceptual space (e.g., that has a similar shape or sound) will be “pulled into the attractor”, with the network state ultimately converging on a pattern that represents that object. This “perceptual magnet” effect can be observed in psychophysical results, which show that discrimination between stimuli that fall within a boundary is less than that between two stimuli that are equally distant in stimulus parameters but that span a categorical boundary </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_18" title="Daelli, 2010 #4747"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Daelli and Treves, 2010</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. It is important to note that this perceptual categorisation, especially of ambiguous stimuli, is also sensitive to context and top-down influences </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_25" title="Feldman, 2009 #4764"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Feldman et al., 2009</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB"> <span style="mso-spacerun: yes;">&nbsp;</span>– indeed, all perception involves the comparison of bottom-up signals with top-down expectations, or prior probabilities, so as to allow active inference of the objects in the world that are responsible for the pattern of sensory stimulation </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_26" title="Friston, 2010 #4748"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Friston, 2010</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_29" title="Gilbert, 2013 #4768"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Gilbert and Li, 2013</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Linking the visual and auditory attributes of an object requires yet a higher level of integration and abstraction </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_33" title="Kourtzi, 2011 #4750"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Kourtzi and Connor, 2011</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. It is driven by the statistical regularities of experience – when the letter A is seen, it is typically accompanied by the sound </span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">ā, as in hay, or ă, as in cat. The representations of these shapes and sounds are thus reliably contingent and can lead to the development of a higher-level representation, incorporating both elements. </span><span lang="EN-GB">The brain thus builds up cognitive representations of letters as audiovisual objects with characteristic attributes, despite the fact that these are essentially arbitrary pairings between symbols and sounds, determined purely by convention </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_11" title="Blomert, 2010 #4762"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Blomert and Froyen, 2010</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">These processes reinforce each other. Though spoken language is learned much earlier and much more easily than written language, learning to read nevertheless increases the ability to distinguish between phonemes (which are not the natural basic units of speech) </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_11" title="Blomert, 2010 #4762"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Blomert and Froyen, 2010</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_21" title="Dehaene, 2010 #2421"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Dehaene et al., 2010</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Conversely, phonetic representations are involved in strengthening categorical representations of graphemes </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_14" title="Brem, 2010 #2552"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Brem et al., 2010</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. The process of forming these associations is quite protracted, taking years to reach a level of perceptual expertise that is effectively automatic, as demonstrated by cross-modal mismatch negativity signals </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_10" title="Blomert, 2010 #2579"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Blomert, 2010</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. The development of such automaticity is lacking in dyslexia, presumably contributing to the fact that reading remains effortful despite extensive training.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In this model of schema formation, any areas that are reliably co-activated will be incorporated into the schema of an object, as supramodal areas monitor patterns of co-activation across many lower areas and represent the statistical regularities of such contingencies. This leads to a model of synaesthesia whereby innate differences in brain wiring produce internally generated percepts, which, over time, are incorporated through the normal processes of cross-modal learning into the schemas of the inducing objects. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">A model unifying innate differences with learning processes</span></b></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This model of associative synaesthesia requires in the first place some intrinsic cross-activation of additional areas not normally activated by particular objects (an innate difference between synaesthetes and non-synaesthetes). For letters, this might be an area representing colour, for example (but the idea can be readily extended to other forms). If such an area is topographically interconnected with say the grapheme area, so that nearby neurons in the first area project to nearby neurons in the second area </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_3" title="Bargary, 2008 #2248"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Bargary and Mitchell, 2008</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">, then activation of the pattern of neuronal firing that represents any particular letter will necessarily cross-activate some (arbitrary) pattern of neuronal firing in the colour area </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_15" title="Brouwer, 2009 #4079"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Brouwer and Heeger, 2009</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_35" title="Li, 2014 #4771"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Li et al., 2014</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Given that the colour areas mature much earlier than the grapheme area </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_6" title="Batardiere, 2002 #1079"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Batardiere et al., 2002</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_12" title="Bourne, 2006 #1083"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Bourne and Rosa, 2006</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_20" title="Dehaene, 2007 #1492"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Dehaene and Cohen, 2007</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">, such patterns will likely evolve towards a set of attractor states that already represent specific colours </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_15" title="Brouwer, 2009 #4079"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Brouwer and Heeger, 2009</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_35" title="Li, 2014 #4771"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Li et al., 2014</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. This may or may not lead to a conscious and vivid percept of colour, but should at least lead to the activation of the concept of a colour. Over time, with extensive repetition, this internally generated sensory property will come to be incorporated into the schema of that letter, becoming as much a part of the concept of the letter as its shape(s) and sound(s). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In this model, without any other influences, the particular pairings that emerge would be expected to be largely arbitrary – dependent on the particular cross-connectivity at the anatomical level. Such a model could explain observed second-order trends, whereby similarly shaped letters tend to have similar colours within individual synaesthetes, even though these colours differ across synaesthetes </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_52" title="Watson, 2012 #4758"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Watson et al., 2012</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. The letters E and F, for example, are often similarly coloured, which would be expected from an arbitrary topographic mapping between areas representing shape space and colour space </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_13" title="Brang, 2011 #4744"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Brang et al., 2011</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In addition, one can imagine how the pairings might be influenced by characteristics that affect the <i style="mso-bidi-font-style: normal;">types</i> of neural patterns representing specific letters or colours </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_16" title="Chiou, 2014 #4745"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Chiou and Rich, 2014</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_22" title="Deroy, 2013 #4735"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Deroy and Spence, 2013a</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_50" title="Ward, 2006 #1233"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Ward et al., 2006</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_52" title="Watson, 2012 #4758"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Watson et al., 2012</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. For example, there could be some correspondences between the states representing higher frequency letters and those representing higher intensity colours (such as the proportion of neurons within the area that are recruited to the representational pattern or some dynamical property of the pattern), which would make pairings between members of those two types more likely to emerge. While speculative, this kind of scenario may provide an explanation of cross-sensory trends that do not rely on semantic information but reflect some currently unknown representational parameters that hold across modalities.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">As with the pairings between graphemes and phonemes that emerge during learning to read, synaesthetic pairings also take a long to coalesce. Simner and colleagues found in a longitudinal study of children an increase in both the number and stability of synaesthetic correspondences between letters and colours at age 7/8 compared to age 6/7 </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_47" title="Simner, 2009 #4756"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Simner et al., 2009</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB"> and more again at age 10/11 </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_46" title="Simner, 2013 #4765"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Simner and Bain, 2013</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Importantly for this model, this protracted period of consolidation leaves the opportunity for semantic associations to influence the ultimate outcome, in the same way that they do when learning the attributes of any object. Such influences could explain the observed trends in specific pairings mentioned above. For example, when a synaesthete is learning the letter B, and their colour area is being cross-activated in some arbitrary pattern, the semantic relationship between B and “blue” may prime the neuronal pattern representing blue, making it more likely for the network to move toward that attractor state, which will in turn be reinforced by each such co-activation. This can be interpreted in a Bayesian context as top-down signals conveying a prior probability of “blue”, in the context of the letter B, which, to a greater or lesser extent across individuals, will tend to over-ride the bottom-up sensory information, biasing the incorporation of a consistent association with this colour into the emerging schema of the letter. It is not difficult to see how such semantic influences could act in other kinds of synaesthesia – for example, if the numbers 1 to 12 are regularly seen in clock face arrangement, that may influence the spatial pattern that emerges in an individual’s number line. (It will be interesting to see whether this trend changes as clock faces become rarer). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In this way, the particular synaesthetic associations that emerge through this protracted process can be biased by top-down semantic processes, without being entirely determined by them, reflecting observed trends rather than rules of associations. Fundamentally, this means that while such semantic processes may affect the outcome, they are not the prime drivers of the phenomenon of synaesthesia. The condition of synaesthesia is thus not <i style="mso-bidi-font-style: normal;">caused by</i>learning, and there is certainly no reason to think of it as having a <i style="mso-bidi-font-style: normal;">purpose</i> in facilitating learning. It may have that effect, but it is a conceptual mistake to interpret that as a reason for its existence.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The difference that makes a difference, in determining why some people get synaesthesia and others do not, is genetic (clearly so in many cases and likely so in others). The model of cross-activation at some level of the perceptual hierarchy remains a parsimonious one for the mechanism through which these genetic differences mediate their primary effects </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_3" title="Bargary, 2008 #2248"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Bargary and Mitchell, 2008</span></a><span style="mso-no-proof: yes;">; </span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_31" title="Hubbard, 2011 #4000"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Hubbard et al., 2011</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">, and has at least general support from many neuroimaging studies </span><span lang="EN-GB"><span style="mso-no-proof: yes;">(</span><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_42" title="Rouw, 2011 #4027"><span style="color: windowtext; mso-no-proof: yes; text-decoration: none; text-underline: none;">Rouw et al., 2011</span></a><span style="mso-no-proof: yes;">)</span></span><span lang="EN-GB">. Whether this involves primary changes in structural or functional connectivity remains an open question, but in either case, the outcome is an altered sensory experience, with some internally generated percept that gets assimilated into the schemas of the inducing objects through normal processes of multisensory learning. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This model is subtly but importantly different from ones that explain synaesthesia on the basis of only an acute difference between the brains of synaesthetes and non-synaesthetes. For some synaesthetes, such as audiovisual synaesthetes for whom new sounds induce a vivid visual percept, there may – perhaps must – be some ongoing sensory cross-talk. But for associators, their synaesthetic experiences may arise not because their brain wiring <i style="mso-bidi-font-style: normal;">is</i>slightly different, but because that difference existed over development, while the person was learning various categories of objects. An interesting possibility that may link the phenomenologically distinct forms of projector and associator synaesthesia is that an early state of vivid synaesthesia, which may fade in conscious experience over time (as reported at least anecdotally by some adults), could nevertheless lead to long-lasting conceptual associations if it were present during this learning period. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The theoretical framework presented here is consistent with both an innate difference as the fundamental driver of the condition of synaesthesia, and with semantic and experiential influences on the eventual phenotype that emerges. In particular, it proposes that the internally generated synaesthetic percepts are treated similar to other sensory information as the brain is learning the sensory attributes of objects and developing schemas to conceptually link them.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">References</span></b></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_1"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Asano, M., and Yokosawa, K. (2013). Grapheme learning and grapheme-color synesthesia: toward a comprehensive model of grapheme-color association. Frontiers in human neuroscience<i style="mso-bidi-font-style: normal;"> 7</i>, 757.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_2"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Asher, J.E., Lamb, J.A., Brocklebank, D., Cazier, J.B., Maestrini, E., Addis, L., Sen, M., Baron-Cohen, S., and Monaco, A.P. (2009). A whole-genome scan and fine-mapping linkage study of auditory-visual synesthesia reveals evidence of linkage to chromosomes 2q24, 5q33, 6p12, and 12p12. Am J Hum Genet<i style="mso-bidi-font-style: normal;"> 84</i>, 279-285.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_3"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Bargary, G., and Mitchell, K.J. (2008). Synaesthesia and cortical connectivity. Trends Neurosci<i style="mso-bidi-font-style: normal;"> 31</i>, 335-342.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_4"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Barnett, K.J., Finucane, C., Asher, J.E., Bargary, G., Corvin, A.P., Newell, F.N., and Mitchell, K.J. (2008). Familial patterns and the origins of individual differences in synaesthesia. Cognition<i style="mso-bidi-font-style: normal;">106</i>, 871-893.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_5"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Baron-Cohen, S., Burt, L., Smith-Laittan, F., Harrison, J., and Bolton, P. (1996). Synaesthesia: prevalence and familiality. Perception<i style="mso-bidi-font-style: normal;"> 25</i>, 1073-1079.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_6"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Batardiere, A., Barone, P., Knoblauch, K., Giroud, P., Berland, M., Dumas, A.M., and Kennedy, H. (2002). Early specification of the hierarchical organization of visual cortical areas in the macaque monkey. Cereb Cortex<i style="mso-bidi-font-style: normal;">12</i>, 453-465.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_7"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Bavelier, D., and Neville, H.J. (2002). Cross-modal plasticity: where and how? Nat Rev Neurosci<i style="mso-bidi-font-style: normal;"> 3</i>, 443-452.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_8"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Behrmann, M., and Avidan, G. (2005). Congenital prosopagnosia: face-blind from birth. Trends Cogn Sci<i style="mso-bidi-font-style: normal;"> 9</i>, 180-187.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_9"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Binder, J.R., and Desai, R.H. (2011). The neurobiology of semantic memory. Trends in cognitive sciences<i style="mso-bidi-font-style: normal;"> 15</i>, 527-536.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_10"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Blomert, L. (2010). The neural signature of orthographic–phonological binding in successful and failing reading development. Neuroimage, doi:10.1016/j.neuroimage.2010.1011.1003.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_11"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Blomert, L., and Froyen, D. (2010). Multi-sensory learning and learning to read. International journal of psychophysiology : official journal of the International Organization of Psychophysiology<i style="mso-bidi-font-style: normal;"> 77</i>, 195-204.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_12"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Bourne, J.A., and Rosa, M.G. (2006). Hierarchical development of the primate visual cortex, as revealed by neurofilament immunoreactivity: early maturation of the middle temporal area (MT). Cereb Cortex<i style="mso-bidi-font-style: normal;"> 16</i>, 405-414.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_13"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Brang, D., Rouw, R., Ramachandran, V.S., and Coulson, S. (2011). Similarly shaped letters evoke similar colors in grapheme-color synesthesia. Neuropsychologia<i style="mso-bidi-font-style: normal;"> 49</i>, 1355-1358.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_14"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Brem, S., Bach, S., Kucian, K., Guttorm, T.K., Martin, E., Lyytinen, H., Brandeis, D., and Richardson, U. (2010). Brain sensitivity to print emerges when children learn letter-speech sound correspondences. Proc Natl Acad Sci U S A<i style="mso-bidi-font-style: normal;"> 107</i>, 7939-7944.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_15"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Brouwer, G.J., and Heeger, D.J. (2009). Decoding and reconstructing color from responses in human visual cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience<i style="mso-bidi-font-style: normal;"> 29</i>, 13992-14003.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_16"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Chiou, R., and Rich, A.N. (2014). The role of conceptual knowledge in understanding synaesthesia: Evaluating contemporary findings from a "hub-and-spokes" perspective. Front Psychol<i style="mso-bidi-font-style: normal;"> 5</i>, 105.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_17"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Chiou, R., Sowman, P.F., Etchell, A.C., and Rich, A.N. (2014). A conceptual lemon: theta burst stimulation to the left anterior temporal lobe untangles object representation and its canonical color. Journal of Cognitive Neuroscience<i style="mso-bidi-font-style: normal;"> 26</i>, 1066-1074.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_18"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Daelli, V., and Treves, A. (2010). Neural attractor dynamics in object recognition. Experimental brain research<i style="mso-bidi-font-style: normal;"> 203</i>, 241-248.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_19"><span lang="EN-GB" style="font-family: &quot;helvetica&quot;; mso-no-proof: yes;">De Renzi, M.</span></a><span style="mso-bookmark: _ENREF_19;"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"> (</span></span><span style="mso-bookmark: _ENREF_19;"><span lang="EN-GB" style="font-family: &quot;helvetica&quot;; mso-no-proof: yes;">2000</span></span><span style="mso-bookmark: _ENREF_19;"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">). </span></span><span style="mso-bookmark: _ENREF_19;"><span lang="EN-GB" style="font-family: &quot;helvetica&quot;; mso-no-proof: yes;">Disorders of visual recognition.</span></span><span style="mso-bookmark: _ENREF_19;"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"> </span></span><span style="mso-bookmark: _ENREF_19;"><span lang="EN-GB" style="font-family: &quot;helvetica&quot;; mso-no-proof: yes;">Semin Neurol</span></span><span style="mso-bookmark: _ENREF_19;"><i style="mso-bidi-font-style: normal;"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"> </span></i></span><span style="mso-bookmark: _ENREF_19;"><i style="mso-bidi-font-style: normal;"><span lang="EN-GB" style="font-family: &quot;helvetica&quot;; mso-no-proof: yes;">20</span></i></span><span style="mso-bookmark: _ENREF_19;"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">, </span></span><span style="mso-bookmark: _ENREF_19;"><span lang="EN-GB" style="font-family: &quot;helvetica&quot;; mso-no-proof: yes;">479-485</span></span><span style="mso-bookmark: _ENREF_19;"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">.</span></span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_20"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Dehaene, S., and Cohen, L. (2007). Cultural recycling of cortical maps. Neuron<i style="mso-bidi-font-style: normal;"> 56</i>, 384-398.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_21"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Dehaene, S., Pegado, F., Braga, L.W., Ventura, P., Filho, G.N., Jobert, A., Dehaene-Lambertz, G., Kolinsky, R., Morais, J., and Cohen, L. (2010). How Learning to Read Changes the Cortical Networks for Vision and Language. Science.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_22"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Deroy, O., and Spence, C. (2013a). Are we all born synaesthetic? Examining the neonatal synaesthesia hypothesis. Neuroscience and biobehavioral reviews<i style="mso-bidi-font-style: normal;"> 37</i>, 1240-1253.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_23"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Deroy, O., and Spence, C. (2013b). Why we are not all synesthetes (not even weakly so). Psychonomic bulletin &amp; review<i style="mso-bidi-font-style: normal;"> 20</i>, 643-664.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_24"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Duchaine, B., Germine, L., and Nakayama, K. (2007). Family resemblance: ten family members with prosopagnosia and within-class object agnosia. Cogn Neuropsychol<i style="mso-bidi-font-style: normal;"> 24</i>, 419-430.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_25"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Feldman, N.H., Griffiths, T.L., and Morgan, J.L. (2009). The influence of categories on perception: explaining the perceptual magnet effect as optimal statistical inference. Psychological review<i style="mso-bidi-font-style: normal;"> 116</i>, 752-782.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_26"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Friston, K. (2010). The free-energy principle: a unified brain theory? Nature reviews Neuroscience<i style="mso-bidi-font-style: normal;"> 11</i>, 127-138.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_27"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Galton, F. (1883). Enquiries into the Human Faculty and its Development. London: Everyman.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_28"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Ghazanfar, A.A., and Schroeder, C.E. (2006). Is neocortex essentially multisensory? Trends in cognitive sciences<i style="mso-bidi-font-style: normal;"> 10</i>, 278-285.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_29"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Gilbert, C.D., and Li, W. (2013). Top-down influences on visual processing. Nature reviews Neuroscience<i style="mso-bidi-font-style: normal;"> 14</i>, 350-363.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_30"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Hebb, D.O. (1949). The Organization of Behavior: A Neuropsychological Theory. . New York: Wiley and Sons.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_31"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Hubbard, E.M., Brang, D., and Ramachandran, V.S. (2011). The cross-activation theory at 10. Journal of neuropsychology<i style="mso-bidi-font-style: normal;"> 5</i>, 152-177.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_32"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Hubbard, E.M., and Ramachandran, V.S. (2005). Neurocognitive mechanisms of synesthesia. Neuron<i style="mso-bidi-font-style: normal;"> 48</i>, 509-520.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_33"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Kourtzi, Z., and Connor, C.E. (2011). Neural representations for object perception: structure, category, and adaptive coding. Annual review of neuroscience<i style="mso-bidi-font-style: normal;"> 34</i>, 45-67.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_34"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Kravitz, D.J., Saleem, K.S., Baker, C.I., Ungerleider, L.G., and Mishkin, M. (2013). The ventral visual pathway: an expanded neural framework for the processing of object quality. Trends in cognitive sciences<i style="mso-bidi-font-style: normal;"> 17</i>, 26-49.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_35"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Li, M., Liu, F., Juusola, M., and Tang, S. (2014). Perceptual color map in macaque visual area V4. The Journal of neuroscience : the official journal of the Society for Neuroscience<i style="mso-bidi-font-style: normal;"> 34</i>, 202-217.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_36"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Mitchell, K.J. (2011). Curiouser and curiouser: genetic disorders of cortical specialization. Curr Opin Genet Dev.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_37"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Mitchell, K.J. (2013). Synaesthesia and cortical connectivity – a neurodevelopmental perspective. In the Oxford Handbook of Synaesthesia (Eds: J Simner and E Hubbard).</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_38"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Mroczko-Wasowicz, A., and Nikolic, D. (2014). Semantic mechanisms may be responsible for developing synesthesia. Frontiers in human neuroscience<i style="mso-bidi-font-style: normal;">8</i>, 509.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_39"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Nijboer, T.C., van Zandvoort, M.J., and de Haan, E.H. (2007). A familial factor in the development of colour agnosia. Neuropsychologia<i style="mso-bidi-font-style: normal;"> 45</i>, 1961-1965.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_40"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Qin, W., and Yu, C. (2013). Neural pathways conveying novisual information to the visual cortex. Neural plasticity<i style="mso-bidi-font-style: normal;"> 2013</i>, 864920.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_41"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Rich, A.N., Bradshaw, J.L., and Mattingley, J.B. (2005). A systematic, large-scale study of synaesthesia: implications for the role of early experience in lexical-colour associations. Cognition<i style="mso-bidi-font-style: normal;"> 98</i>, 53-84.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_42"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Rouw, R., Scholte, H.S., and Colizoli, O. (2011). Brain areas involved in synaesthesia: a review. Journal of neuropsychology<i style="mso-bidi-font-style: normal;"> 5</i>, 214-242.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_43"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Schmid, Y., Enzler, F., Gasser, P., Grouzmann, E., Preller, K.H., Vollenweider, F.X., Brenneisen, R., Muller, F., Borgwardt, S., and Liechti, M.E. (2014). Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects. Biological psychiatry.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_44"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Simner, J. (2007). Beyond perception: synaesthesia as a psycholinguistic phenomenon. Trends Cogn Sci<i style="mso-bidi-font-style: normal;"> 11</i>, 23-29.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_45"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Simner, J. (2012). Defining synaesthesia. Br J Psychol.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_46"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Simner, J., and Bain, A.E. (2013). A longitudinal study of grapheme-color synesthesia in childhood: 6/7 years to 10/11 years. Frontiers in human neuroscience<i style="mso-bidi-font-style: normal;"> 7</i>, 603.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_47"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Simner, J., Harrold, J., Creed, H., Monro, L., and Foulkes, L. (2009). Early detection of markers for synaesthesia in childhood populations. Brain : a journal of neurology<i style="mso-bidi-font-style: normal;"> 132</i>, 57-64.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_48"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Sinke, C., Halpern, J.H., Zedler, M., Neufeld, J., Emrich, H.M., and Passie, T. (2012). Genuine and drug-induced synesthesia: a comparison. Consciousness and cognition<i style="mso-bidi-font-style: normal;"> 21</i>, 1419-1434.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_49"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">van Zandvoort, M.J., Nijboer, T.C., and de Haan, E. (2007). Developmental colour agnosia. Cortex<i style="mso-bidi-font-style: normal;"> 43</i>, 750-757.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_50"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Ward, J., Huckstep, B., and Tsakanikos, E. (2006). Sound-colour synaesthesia: to what extent does it use cross-modal mechanisms common to us all? Cortex<i style="mso-bidi-font-style: normal;"> 42</i>, 264-280.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_51"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Ward, J., and Simner, J. (2005). Is synaesthesia an X-linked dominant trait with lethality in males? Perception<i style="mso-bidi-font-style: normal;"> 34</i>, 611-623.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_52"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Watson, M.R., Akins, K.A., and Enns, J.T. (2012). Second-order mappings in grapheme-color synesthesia. Psychonomic bulletin &amp; review<i style="mso-bidi-font-style: normal;"> 19</i>, 211-217.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_53"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Watson, M.R., Akins, K.A., Spiker, C., Crawford, L., and Enns, J.T. (2014). Synesthesia and learning: a critical review and novel theory. Frontiers in human neuroscience<i style="mso-bidi-font-style: normal;"> 8</i>, 98.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_54"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Witthoft, N., and Winawer, J. (2006). Synesthetic colors determined by having colored refrigerator magnets in childhood. Cortex; a journal devoted to the study of the nervous system and behavior<i style="mso-bidi-font-style: normal;"> 42</i>, 175-183.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><a href="https://www.blogger.com/null" name="_ENREF_55"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;">Yon, D., and Press, C. (2014). Back to the future: synaesthesia could be due to associative learning. Front Psychol<i style="mso-bidi-font-style: normal;"> 5</i>, 702.</span></a><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-hansi-font-family: Cambria; mso-no-proof: yes;"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2016/05/schema-formation-in-synaesthesia.htmlnoreply@blogger.com (Kevin Mitchell)1tag:blogger.com,1999:blog-6146376483374589779.post-7141674052665618451Wed, 04 May 2016 19:58:00 +00002016-05-04T12:58:32.728-07:00autismclinical geneticscommon variantscopy number variantsGCTAGWASheritabilitypsychiatric geneticsrare mutationsschizophreniatherapiesGenetics in psychiatry - hope or hype?<div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-520092929 1073786111 9 0 415 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> <br /><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;"></span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;"></span><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">This blog was inspired by discussions I have been having with <a href="https://twitter.com/AllenFrancesMD?ref_src=twsrc^google|twcamp^serp|twgr^author">Allen Frances</a> and also partly in response to some blogs he was written about the role of genetics in psychiatry. He is, I think it's fair to say, highly skeptical that genetics will be of much use in psychiatry, as he discusses <a href="https://www.psychologytoday.com/blog/saving-normal/201604/what-you-need-know-about-the-genetics-mental-disorders">here</a>. His jaded view stems partly from the relentless hype which accompanies a lot of announcements of large-scale genetics projects or of their results, and also from a perceived lack of progress of these efforts in explaining genetic risk for psychiatric disorders. With the rapid pace of developments in psychiatric genetics, it is worth taking a beat to consider what we know and to try and separate the hope from the hype. </span> </div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Psychiatric disorders are highly <a href="https://en.wikipedia.org/wiki/Heritability">heritable</a>.</span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;"> Twin and adoption studies have demonstrated conclusively that differences in risk for these conditions are at least partly, and in many cases largely, due to genetic differences. Indeed, psychiatric disorders are far more heritable than conditions like heart disease or cancer. That is not to say that genetics explains all the risk, but certainly enough of it to make it worthwhile understanding the underlying biological mechanisms. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Genetic risk for mental illness overlaps clinical boundaries.</span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;"> Having a relative with a diagnosis of say, schizophrenia, increases an individual’s statistical risk not just of that disorder, but also of bipolar disorder, autism, depression, ADHD, epilepsy, intellectual disability and many others. Moreover, specific mutations often manifest in diverse clinical diagnoses across individuals. From an etiological perspective, the diagnostic categories in the <a href="https://en.wikipedia.org/wiki/DSM-5">DSM</a> thus do not represent <a href="https://en.wikipedia.org/wiki/Natural_kind">natural kinds</a>. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Most of the genetic risk does not lie in common variants.</span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;"> This should not come as a surprise. Any genetic variant that increases risk of psychiatric disorders should be strongly selected against because such disorders greatly increase mortality and reduce fecundity (number of offspring). While <a href="https://en.wikipedia.org/wiki/Genome-wide_association_study">genome-wide association studies</a> have identified some, indeed <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=25056061">many</a>, common variants associated with risk for conditions like schizophrenia, or shared risk across disorders, these collectively explain very little (~7%) of the overall genetic risk. (Even techniques such as <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014363/">genome-wide complex trait analysis</a> suggest only about 25% of genetic risk for schizophrenia is tagged by common variants. That is, if you take estimates from such techniques at face value, which I do not, for reasons <a href="http://www.wiringthebrain.com/2013/11/the-dark-arts-of-statistical-genomics.html">I discuss here</a>). Common variants likely contribute to modifying effects of genetic background but clearly do not explain disease risk by themselves. The oft-repeated line that disorders like schizophrenia are “due to the cumulative effects of many variants of small effect” is thus not supported – at least this is not a complete description of the genetic architecture.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Many cases are caused by rare mutations.</span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;"> It has been known for decades that some specific genetic syndromes, such as <a href="https://en.wikipedia.org/wiki/Fragile_X_syndrome">Fragile X</a> syndrome or <a href="https://en.wikipedia.org/wiki/DiGeorge_syndrome">velocardiofacial</a>syndrome (now called 22q11.2 deletion syndrome), convey very high risk of psychiatric disorders, such as autism or schizophrenia. It was thought by many that these conditions were somehow exceptional and not relevant to the remaining cases of idiopathic and non-syndromic cases, which were believed, on rather <a href="http://www.ncbi.nlm.nih.gov/pubmed/20380786">flimsy grounds</a>, to have a very different genetic architecture. It turns out that, far from being exceptional, those long-known genetic disorders are perfect exemplars of the genetic architecture of psychiatric conditions. The development of<a href="https://en.wikipedia.org/wiki/Comparative_genomic_hybridization#Array-CGH"> chromosomal microarray</a> technologies and <a href="https://en.wikipedia.org/wiki/Exome_sequencing">whole-exome</a> or whole-genome sequencing has led to the discovery of dozens, indeed now<a href="http://eu.wiley.com/WileyCDA/WileyTitle/productCd-1118524888.html"> hundreds</a>, of similar rare genetic disorders that predispose to very high risk of mental illness. More and more such disorders are being recognised as additional cases are sequenced. Clinical categories like autism or schizophrenia are, from an etiological point of view, umbrella terms encompassing hundreds of rare genetic disorders.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Sequencing can reveal rare mutations</span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">. Identifying such rare conditions will become easier as more and more cases and controls are sequenced, giving us greater power to discriminate pathogenic mutations from the background of rare mutations that we all carry. These efforts have only just begun but we are already seeing them yield results. Already 20-25% of cases of <a href="http://www.ncbi.nlm.nih.gov/pubmed/23425232">autism</a> and ~10% of cases of <a href="http://www.ncbi.nlm.nih.gov/pubmed/23813976">schizophrenia</a>can be ascribed to a primary genetic mutation – a huge increase in diagnostic yield from just a couple years ago.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Genetic causation is complex.</span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;"> Describing these as rare genetic disorders is not meant to imply simple genetic causation. All the known mutations can give rise to a wide variety of effects in different individuals and are often carried by clinically unaffected people. The pathogenic effects of particular mutations can be modified by other genetic variants that any individual may carry, whether common or rare. There is nothing unusual in this scenario, however – even the most classic Mendelian disorders, such as cystic fibrosis or Huntington’s disease, are subject to <a href="https://genomebiology.biomedcentral.com/articles/10.1186/gb-2012-13-1-237">modifying effects from other genes</a>. </span><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">Specifically, we can expect that more severe cases, with earlier onset, will be more likely due to single genetic mutations, often arising <a href="http://www.nature.com/nrg/journal/v13/n8/full/nrg3241.html">de novo</a>, while less severe cases, with later onset, will include a bigger contribution from inherited mutations and more interplay between multiple mutations in any given individual.&nbsp;</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Non-genetic factors are also important.</span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;"> The variation in phenotype often observed between monozygotic twins also shows that non-genetic factors – such as <a href="http://www.wiringthebrain.com/2009/06/nature-nurture-and-noise.html">stochastic processes of brain development</a> or later experience – can have large effects on the phenotypic outcome associated with any given genotype. These observations place important limits on the ability to genetically predict disease risk in anything other than a probabilistic fashion.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Genetic diagnoses are still useful</span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">. Even with the complexities mentioned above, it will still often be possible to identify a <span id="goog_437695804"></span>primary causal mutation<span id="goog_437695805"></span> in individual patients. </span><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">(<a href="http://www.wiringthebrain.com/2014/01/on-genetic-causality-forwards-and.html">See here</a> for a more detailed discussion of inferences of genetic causality). </span><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Such diagnoses are immediately useful in many ways – they give a definitive etiological diagnosis that complements the often more fluid diagnoses based on symptoms; they allow clinicians to group patients and define new syndromes; they empower patients and their families to help drive such efforts; they inform on genetic risk to subsequent offspring; in some cases they may already give information on likely responsiveness to treatments. Just as importantly, they give biological entry points to dissect the underlying pathogenic mechanisms and hopefully develop new treatments.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Genetics is just the first step</span></b><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">. There is a regrettable culture of hype around much of science these days, driven by the need to promise near-term translational impact to secure funding. This has certainly been the case in the field of psychiatric genetics. It is crucial to recognise, and, in my opinion, to state publicly, that identifying pathogenic mutations is just the first step in what will be a very long journey to develop new therapeutics. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">The drug discovery model that has worked so well for disorders like cancer will simply not work for most of the rare disorders causing psychiatric illness. In cancer, the pathogenic effects of mutations arise at the cellular level – they directly affect the processes of proliferation and differentiation that drive the disease. Identifying a primary genetic mutation can thus directly implicate a particular biochemical pathway as a suitable drug target. Even when that is the case it is still a hugely difficult task to actually develop a new drug that works. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">For psychiatric disorders, the difficulty of that task will be multiplied many-fold, because the answer will not come at the level of molecular biology or biochemistry. We must figure out how changes at those levels lead to alterations at the level of neural circuits and systems, which emerge only via cascading and indirect effects through the complex and dynamic processes of neural and cognitive development. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Predictions of new treatments in the short term should thus be tempered with a good dose of humility. </span><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">Genetics will not suggest new pharmaceutical approaches by itself. What it will do is enable more insightful neuroscience by providing</span><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;"> crucial entry points to elucidate the underlying pathobiology. This is especially true for high-risk mutations which can be <a href="http://bmcbiol.biomedcentral.com/articles/10.1186/1741-7007-9-76">modelled directly in cells or animals</a> to elucidate the pathways by which mutation of specific genes lead ultimately to neural circuit and system dysfunction. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Genetics is thus the crucial first step on what will be a long journey to better understand the causes of mental illness. Indeed, not </span><span style="font-family: Calibri; mso-ansi-language: EN-US; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Calibri; mso-hansi-theme-font: major-latin;">only do I think a genetic approach will be productive, I think it is the <i>only</i> thing that will be. Certainly nothing else has worked – psychiatry has made essentially no progress otherwise over the last sixty years or more. Maybe that’s a bit harsh, but we have certainly had no biological insights that have yielded new drugs with new mechanisms of action over that time-frame. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">A key reason why is that we have had no way to dissect the cryptic heterogeneity of these disorders. Genetics not only illustrates that heterogeneity but provides the means to distinguish patients based on underlying etiology. This will entail a real paradigm shift in psychiatry – from treating all patients with similar symptoms as monolithic groups, to recognising that such symptoms can have very diverse causes and grouping patients instead on the basis of genetic etiology. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-hansi-theme-font: major-latin;">Thus, while I agree with Allen Frances that the attendant hype around genetics in psychiatry is misplaced and unhelpful, I am much more optimistic than he is that this approach will pay off. These are genetic disorders. Their inheritance may be complex but is not infinitely so or intractably so. We can and will make progress – but it will take a lot of subsequent research to turn that progress into new treatments. </span></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2016/05/genetics-in-psychiatry-hope-or-hype.htmlnoreply@blogger.com (Kevin Mitchell)6tag:blogger.com,1999:blog-6146376483374589779.post-4021938571108045512Tue, 12 Apr 2016 13:51:00 +00002016-04-12T06:51:06.422-07:00common variantsGCTAgenetic architectureGWASpolygenicrare mutationsschizophreniaIs a polygenic model of schizophrenia genetics really proven? <div dir="ltr" style="text-align: left;" trbidi="on"><span style="font-family: Arial,Helvetica,sans-serif;"> </span><style><!-- /* Font Definitions */ @font-face {font-family:Times; panose-1:2 0 5 0 0 0 0 0 0 0; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1107305727 0 0 415 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">Response to “<a href="http://www.nature.com/mp/journal/v20/n1/abs/mp201494a.html">A joint history of the nature of genetic variation and the nature of schizophrenia</a>”.*</span><span style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">Kenneth Kendler’s article on the nature of genetic variation and the nature of schizophrenia claims that theory and empirical evidence have <i><b>proven the polygenic architecture of this disorder</b></i>. In fact, both theory and data are entirely consistent with a very different model of high genetic heterogeneity, where the disorder is largely caused in individuals by one or a few mutations in any of a large number of genes, incorporating important and complex effects of genetic background.<span style="mso-spacerun: yes;">&nbsp; </span></span><span style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">KK provides a scholarly overview of the history of ideas in these intertwined fields<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_1" title="Kendler, 2014 #4701"><sup><span style="mso-no-proof: yes;">1</span></sup></a>. While historically interesting, the early arguments between biometricians and Mendelians about continuous versus dichotomous traits conflate two distinct questions: (i) what type of genetic variation contributes to the gradual evolution of new species?, and (ii) what type of genetic variation causes disease? There is no reason to expect these to have the same answer and many reasons not to. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">With regard to the genetic architecture of SZ, KK presents the history of various models, from those positing a single major locus to those invoking polygenic mechanisms based on the work of Fisher, Falconer and others. Of course, the single major locus model has long since been rejected and the current debate is really between (i) models of extreme genetic heterogeneity, where the disease is largely caused by one or a small number of rare mutations in each affected individual (in any of a large number of different genes), and (ii) polygenic models involving the combined effects of thousands of common variants that “constitute the gene pool of our species”. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">The only reference KK makes to models of genetic heterogeneity regrettably repeats a commonly held but mistaken notion, i.e., that the (negative) results of linkage analyses for SZ refute the theory that the disorder is a “common pathway for a large number of rare quasi-Mendelian disorders”, based on the idea that multiple linkage peaks would have been found if that were the case. This is demonstrably false. Most SZ linkage studies bundled together many small families, as large multiplex SZ pedigrees are rare. If the disorder shows a high level of genetic heterogeneity, combining families will necessarily obscure real linkage signals<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_2" title="Mitchell, 2011 #3883"><sup><span style="mso-no-proof: yes;">2</span></sup></a>. Recent simulations bear this out: in cases where a disorder is associated with decreased fitness and high genetic heterogeneity, linkage studies are predicted to fail<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_3" title="Agarwala, 2013 #4357"><sup><span style="mso-no-proof: yes;">3</span></sup></a>. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">KK also presents several lines of positive evidence as supporting – <i><b>indeed</b></i> <i><b>proving</b></i> – that the polygenic model of SZ is correct. First, he argues that the existence of a phenotypic continuum between clinically diagnosable SZ and SZ-like personality disorders in first-degree relatives proves a polygenic model. It does not. Many classical single-gene disorders show incomplete penetrance and variable expressivity. In some cases, these are due to modifier genes in the background, but – as for SZ itself – phenotypes often vary substantially even between monozygotic twins. What these observations really highlight is that psychiatric diagnostic categories do not represent distinct biological phenotypes, but only one of a range of possible outcomes. The clinical and etiological overlap between SZ and other neurodevelopmental disorders, including autism, epilepsy and intellectual disability reinforces this point<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_4" title="Moreno-De-Luca, 2013 #4346"><sup><span style="mso-no-proof: yes;">4</span></sup></a>. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">Second, KK claims that recent genome-wide association studies and related analyses “have shown that for schizophrenia, Fisher’s model is largely correct”. This interpretation is not warranted by the data. A recent, very large-scale GWAS identified 108 loci with common single-nucleotide polymorphisms (SNPs) showing positive association signals with disease (higher frequency in cases than controls)<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_5" title="Consortium, 2014 #4702"><sup><span style="mso-no-proof: yes;">5</span></sup></a>. However, GWAS signals do not identify causal variants or inform as to their allelic frequency. Numerous examples of synthetic associations caused by rare mutations have been demonstrated and the fact that rare mutations in many of the loci implicated are known to confer high risk for neuropsychiatric diseases supports this possibility<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_5" title="Consortium, 2014 #4702"><sup><span style="mso-no-proof: yes;">5</span></sup></a>. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">But even if the causal variants are common, this does not imply that the polygenic model is correct. The GWAS signal is a population-level average statistic and does not speak to how these variants <a href="http://www.wiringthebrain.com/2015/11/what-do-gwas-signals-mean.html">act in individuals</a>. Rather than acting in purely polygenic fashion – a <a href="https://genomebiology.biomedcentral.com/articles/10.1186/gb-2012-13-1-237">hypothetical mechanism</a> never actually demonstrated to cause disease – common variants may instead act as important modifiers of risk due to rare variants or environmental perturbations – a perfectly well-established mechanism (e.g., ref. <a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_6" title="Alves, 2013 #4497"><sup><span style="mso-no-proof: yes;">6</span></sup></a>). </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">Genome-Wide Complex Trait Analyses also cannot determine the number of contributing loci per individual, the number of causal variants across the population or the frequency of causal variants. This is stated clearly by Lee et al: </span><span lang="GA" style="font-size: 10pt; line-height: 115%;">“</span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">From the analyses we have performed, we cannot estimate a distribution of the allele frequency of causal variants”<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_7" title="Lee, 2012 #4388"><sup><span style="mso-no-proof: yes;">7</span></sup></a>. These analyses merely show (or claim) that extremely small statistical increases in risk can be detected across distant relatedness, presuming the technical assumptions and methods are valid<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_7" title="Lee, 2012 #4388"><sup><span style="mso-no-proof: yes;">7</span></sup></a><sup><span style="mso-no-proof: yes;">,</span></sup><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_8" title="Browning, 2011 #4394"><sup><span style="mso-no-proof: yes;">8</span></sup></a>. In any case, GCTA analyses for SZ show that most genetic risk is NOT associated with common variants. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">Genetic epidemiology at the population level can point to loci of interest but the findings do not restrict or even really inform on the genetic architecture of the disorder <b><i>in individuals</i></b>. The empirical data are perfectly consistent with a model of high genetic heterogeneity, where most cases are associated with one or a small number of high-risk mutations<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_9" title="McClellan, 2007 #1832"><sup><span style="mso-no-proof: yes;">9</span></sup></a>, and where the phenotypic expression of these mutations is affected by genetic background<a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ENREF_10" title="Mitchell, 2012 #3792"><sup><span style="mso-no-proof: yes;">10</span></sup></a>.</span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">Finally, it seems strange to draw moral conclusions about how we should think of or treat people with SZ based on the genetic architecture of the disease. There does not need to be a continuum of risk across the population for healthy people to feel sympathy for those affected. It is very clear, from monozygotic twin concordance rates of ~50%, that those who have SZ were at very high risk of developing it, on average, with the corollary that the majority of the population had effectively zero risk. “Liability” may be normally distributed but that is an imaginary statistical construct – actual risk is clearly <i style="mso-bidi-font-style: normal;">not</i> continuous, under any model of genetic architecture. No moral conclusions derive from that fact. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"><span style="mso-spacerun: yes;">[Postscript: I haven't gone in to all the positive evidence for an important role for rare mutations of large effect in the etiology of SZ, but see here for many examples and more details:</span></span></span><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"><span style="mso-spacerun: yes;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"> <a href="http://biorxiv.org/content/early/2014/09/19/009449">The Genetic Architecture of Neurodevelopmental Disorders</a>.]</span></span> </span></span></span></div><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;">References</span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_1"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">1<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Kendler, K. S. <i style="mso-bidi-font-style: normal;">Molecular Psychiatry</i> <b style="mso-bidi-font-weight: normal;">Advance online publication, 19 August 2014; doi:10.1038/mp.2014.94</b> (2014).</span></a><span style="mso-bookmark: _ENREF_1;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_2"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">2<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Mitchell, K. J. &amp; Porteous, D. J. <i style="mso-bidi-font-style: normal;">Psychol Med</i> <b style="mso-bidi-font-weight: normal;">41</b>, 19-32, doi:S003329171000070X [pii]</span></a><span style="mso-bookmark: _ENREF_2;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bookmark: _ENREF_2;"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">10.1017/S003329171000070X (2011).</span></span><span style="mso-bookmark: _ENREF_2;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_3"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">3<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Agarwala, V., Flannick, J., Sunyaev, S. &amp; Altshuler, D. <i style="mso-bidi-font-style: normal;">Nature genetics</i><b style="mso-bidi-font-weight: normal;">45</b>, 1418-1427, doi:10.1038/ng.2804 (2013).</span></a><span style="mso-bookmark: _ENREF_3;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_4"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">4<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Moreno-De-Luca, A.<i style="mso-bidi-font-style: normal;"> et al.</i> <i style="mso-bidi-font-style: normal;">Lancet neurology</i> <b style="mso-bidi-font-weight: normal;">12</b>, 406-414, doi:10.1016/S1474-4422(13)70011-5 (2013).</span></a><span style="mso-bookmark: _ENREF_4;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_5"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">5<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Consortium, <i style="mso-bidi-font-style: normal;">Nature</i> <b style="mso-bidi-font-weight: normal;">511</b>, 421-427, doi:10.1038/nature13595 (2014).</span></a><span style="mso-bookmark: _ENREF_5;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_6"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">6<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Alves, M. M.<i style="mso-bidi-font-style: normal;"> et al.</i> <i style="mso-bidi-font-style: normal;">Dev Biol</i> <b style="mso-bidi-font-weight: normal;">382</b>, 320-329, doi:10.1016/j.ydbio.2013.05.019 (2013).</span></a><span style="mso-bookmark: _ENREF_6;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_7"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">7<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Lee, S. H.<i style="mso-bidi-font-style: normal;"> et al.</i> <i style="mso-bidi-font-style: normal;">Nature genetics</i> <b style="mso-bidi-font-weight: normal;">44</b>, 247-250, doi:10.1038/ng.1108 (2012).</span></a><span style="mso-bookmark: _ENREF_7;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_8"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">8<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Browning, S. R. &amp; Browning, B. L. <i style="mso-bidi-font-style: normal;">Am J Hum Genet</i> <b style="mso-bidi-font-weight: normal;">89</b>, 191-193; author reply 193-195, doi:10.1016/j.ajhg.2011.05.025 (2011).</span></a><span style="mso-bookmark: _ENREF_8;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_9"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">9<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>McClellan, J. M., Susser, E. &amp; King, M. C. <i style="mso-bidi-font-style: normal;">Br J Psychiatry</i> <b style="mso-bidi-font-weight: normal;">190</b>, 194-199 (2007).</span></a><span style="mso-bookmark: _ENREF_9;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/null" name="_ENREF_10"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">10<span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Mitchell, K. J. <i style="mso-bidi-font-style: normal;">Genome Biol</i> <b style="mso-bidi-font-weight: normal;">13</b>, 237, doi:gb-2012-13-1-237 [pii]</span></a><span style="mso-bookmark: _ENREF_10;"><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; margin-left: .5in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bookmark: _ENREF_10;"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;">10.1186/gb-2012-13-1-237 (2012).</span></span><span style="mso-bookmark: _ENREF_10;"></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;"><span style="mso-spacerun: yes;"><br /></span></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;"><span style="mso-spacerun: yes;"><br /></span></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="font-size: 10.0pt; line-height: 115%; mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria; mso-no-proof: yes;"><span style="mso-spacerun: yes;">* I originally wrote this as a letter to the editor at Molecular Psychiatry, in response to the article referenced by Kenneth Kendler, but they didn't like it, so I just decided to post it here instead.</span></span><span lang="EN-GB" style="font-size: 10pt; line-height: 115%;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="line-height: 115%;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span></div>http://www.wiringthebrain.com/2016/04/is-polygenic-model-of-schizophrenia.htmlnoreply@blogger.com (Kevin Mitchell)2tag:blogger.com,1999:blog-6146376483374589779.post-7982509990860789222Sat, 19 Mar 2016 16:29:00 +00002016-03-19T09:29:54.240-07:00comicscryptic genetic variationevolutiongeneticsmutationrobustnessscicommX-MenThe surprising real genetics behind the X-Men<div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1107305727 0 0 415 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> <br /><div class="MsoNormal"><a href="http://comicvine.gamespot.com/articles/uncanny-x-men-celebrate-in-san-francisco/1100-133071/"><span lang="EN-GB"><img border="0" height="200" src="https://1.bp.blogspot.com/-JetHF2gzLds/Vu10xOZJLVI/AAAAAAAAAu4/vGV1jZMQGjwuIEn8MZtpoLaXGDaygiyhw/s400/X-Men.png" width="400" /></span></a></div><div class="MsoNormal"><span lang="EN-GB">The <a href="https://en.wikipedia.org/wiki/X-Men">X-Men </a>– everyone’s favourite mutants – are hugely popular, thanks to seven feature films since 2000, with more on the way, and to the enormously successful comics that have been running for over 50 years. With that kind of exposure, they can have a real influence on the public perception of genetics, grounded as they are in ideas of mutation and evolution of the “next stage of humanity”. So, is there any real scientific basis underlying these stories? Well, to a geneticist, most of the supposed mutant abilities of the X-Men and their mutant brethren are frankly ludicrous. No matter how mutant you are, the laws of physics will still apply! (Except for Entropy Man of course). But some of them are less far-fetched, reflecting the strange and wonderful world of real-life biology. And underlying them all is a much deeper mechanism that has, in the real world, a profound effect on how mutations contribute to evolution. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The X-Men were created in 1963 by <a href="https://en.wikipedia.org/wiki/Stan_Lee">Stan Lee</a> at <a href="https://en.wikipedia.org/wiki/Marvel_Comics">Marvel comics</a>. He had already done the Fantastic Four and the Hulk and Spider-Man but wanted to create a new team of superheroes, with a bunch of different powers. And when it came to their origin story, he was, by his own admission, just being lazy. He realised he couldn’t have everyone exposed to cosmic rays or gamma rays or bitten by a radioactive spider – you’d quickly run out of radioactive animals to bite people that would be in any way cool – Mosquito-Man or Bed Bug-Man just don’t sound that awesome (though <a href="https://en.wikipedia.org/wiki/Tick_%28comics%29">The Tick</a> has always been a personal favourite). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So, he decided he would simply make them all “mutants” – they were all just born that way. That way </span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">he could have one have lasers coming out of his eyeballs and another able to control the weather and another able to turn into ice and just say it was all down to mutation. </span><span lang="EN-GB"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">He actually wanted to call the comic The Mutants, but he was over-ruled on the basis that no one at the time really knew what mutants were – the word was in the air, perhaps, linked to the ever-present threat of radiation that loomed large in the public consciousness during the Cold War, but it wouldn’t have been widely understood. And it seems from looking at some of their abilities that Stan Lee didn’t really know what mutants are either, because a lot of those powers are just absurd.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">I mean, some animals can manage a dim glow that you can see in the darkest depths of the ocean but lasers out of your eyeballs like <a href="https://en.wikipedia.org/wiki/Cyclops_%28comics%29">Cyclops</a> is a bit of a stretch. Where would the power come from? And while we’re at it, how is he supposed to see anything? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Or controlling magnetism like <a href="https://en.wikipedia.org/wiki/Magneto_%28comics%29">Magneto</a> – again, some animals can emit very weak electromagnetic fields – duck-billed platypuses do that to detect their prey, for example – but the idea that a mutation could let you lift an aircraft carrier is just silly. (It’s inspired silliness, but still). On the other hand, if you want an origin story for a character with the ability to manipulate magnetism, I suppose it beats being bitten by a radioactive platypus.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Many of the other abilities also require suspension of the laws of physics (a big ask for a little change in your DNA), but a few of them actually have some grounding in real biology. </span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><a href="http://marvel.wikia.com/wiki/Ultimate_Wolverine" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://marvel.wikia.com/wiki/Ultimate_Wolverine" border="0" height="320" src="https://4.bp.blogspot.com/-YmRZWeZKLgU/Vu19CXy0nII/AAAAAAAAAvM/gr74UzX8t8wM0_QRp6j42tqv_Bs63qtAw/s320/wolverine.png" width="235" /></a><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Let’s take everyone’s favourite mutant, <a href="https://en.wikipedia.org/wiki/Wolverine_%28character%29">Wolverine</a>. His main power is his super-healing ability, which actually is quite plausible (in kind anyway, if not in degree). There are, in fact, strains of mice called “<a href="http://www.ncbi.nlm.nih.gov/pubmed/24163690">super-healing mice</a>” (AKA </span><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">Murphy Roths Large / lymphoproliferative mouse strain!) </span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">where something very similar has been found. These strains were initially of interest because they are prone to autoimmune disorders. Their super-healing ability was discovered quite by accident when researchers noticed that the ear punches they used to keep track of individual mice were healing over completely! These mice show increased wound healing generally, with much reduced scarring and even more rapid healing of broken bones. It’s still not really known why this is or which genes are responsible, however.</span><span style="font-family: &quot;Times New Roman&quot;; font-size: 10.0pt; mso-ansi-language: EN-US;"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Wolverine is also ferocious (a berserker, in fact), and something like that can also be caused by mutations. In fact, there are many mutations that affect aggressiveness, (having a Y chromosome certainly does), but the ones with the biggest effect in mice are in a gene called <a href="http://www.ncbi.nlm.nih.gov/gene/7101">NR2E1</a>, which is involved in brain development. A line of mice with mutations in this gene are called “<a href="http://www.ncbi.nlm.nih.gov/pubmed/11997145">fierce</a>” because they’re so aggressive, with both males and females viciously attacking other mice or even anyone foolish enough to put their hand in the cage. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"><a href="https://en.wikipedia.org/wiki/Beast_%28comics%29">Beast</a> is another mutant whose abilities are not completely ludicrous. There are mutations that </span></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogmuscle.wordpress.com/2007/07/13/wendy-the-whippet-a-mutant-double-muscled-dog-has-internet-abuzz/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="https://blogmuscle.wordpress.com/2007/07/13/wendy-the-whippet-a-mutant-double-muscled-dog-has-internet-abuzz/" border="0" height="246" src="https://3.bp.blogspot.com/-MtYCK4Em_Nw/Vu14o14YpDI/AAAAAAAAAvA/jhO9o-IHJmArSU_rnJlfsLM_k-f4l4WMA/s320/double%2Bmuscle%2Bdog.jpg" width="320" /></a></div>can make you super-strong, in genes called <a href="https://en.wikipedia.org/wiki/Myostatin">myostatin</a> or <a href="https://en.wikipedia.org/wiki/Activin_and_inhibin">activin</a>, which normally act to restrict muscle growth. When these genes are mutated, in cattle, mice or humans, muscle growth can increase by two-fold or more, with concomitant increases in strength. And there are also mutations that can make you grow hair all over your body (a condition called hypertrichosis, or, less sympathetically, werewolf syndrome). <br /> <div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Now it’s not usually blue hair, like Beast’s, but there is another mutation that does cause shockingly blue skin coloration, in a condition called <a href="https://en.wikipedia.org/wiki/Methemoglobinemia">methemoglobinaemia</a>. It is famous from a particular kindred from the wonderfully named town of Troublesome Creek in the Appalachian mountains of Kentucky. They are known as the “<a href="https://en.wikipedia.org/wiki/Blue_Fugates">blue Fugates</a>”, that being the most common last name in the clan, and they really do have skin close to the colour of <a href="https://en.wikipedia.org/wiki/Mystique_%28comics%29">Mystique</a> or <a href="https://en.wikipedia.org/wiki/Nightcrawler_%28comics%29">Nightcrawler</a>. No signs of shape-shifting or teleportation, though (although you never know with people from Kentucky – they’re tricksy…)</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Let’s see, how about <a href="https://en.wikipedia.org/wiki/Professor_X">Professor X</a>? He’s a telepath, of course, with an ability to read minds and manipulate people. As crazy as it sounds, there is a genetically distinct group of people who are much better than the rest of the population at reading minds – they’re called women. On average, <a href="http://www.amazon.com/The-Essential-Difference-Female-Brains/dp/046500556X">women score higher</a> than men on measures of empathy and performance on tasks like “<a href="https://www.questionwritertracker.com/quiz/61/Z4MK3TKB.html">reading the mind in the eyes test</a>”. People with autism tend to do very poorly on such tests, but so does a sizeable proportion of the general male population. Whether there are people at the other end of the spectrum, with really heightened abilities – super-empathisers – remains unknown, though it seems plausible enough. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">So, overall, most of the X-Men abilities are completely nuts but a few are only wildly exaggerated, like super-strength or super-healing or being blue or hairy. But here’s the thing – all those things arise from mutations in different genes while the X-Men are all supposed to have inherited a mutation in <i style="mso-bidi-font-style: normal;">the same gene</i> – the “<a href="https://en.wikipedia.org/wiki/Mutant_%28Marvel_Comics%29">X gene</a>”, yet they have very different abilities. So how could that be?</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Despite not actually knowing anything about genetics, Lee stumbled onto an idea that actually exists and that, in fact, plays an important role in evolution. There really is a gene that, when mutated, causes all kinds of different effects in different individuals. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">This gene is called <a href="https://en.wikipedia.org/wiki/Hsp90">Hsp90</a> and it encodes what’s known as a “heat shock protein”. Heat shock proteins are turned on in cells when they are under stress – like when you suddenly raise the temperature. Their job is to help the cell deal with that stress and in particular to help other proteins in the cell to fold into the right shapes. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">We have about 20,000 different proteins in our cells, each one encoded by a different gene. Each protein is made from a string of subunits called amino acids – there are twenty different kinds that are strung along in a specific sequence encoded by the DNA sequence of that gene. As each protein is being made, that string of amino acids <a href="https://en.wikipedia.org/wiki/Protein_folding">folds back on itself</a> in a kind of molecular origami, making a complex three-dimensional structure, the shape of which depends on all the forces between all the atoms in those amino acids. The particular 3D shape of each protein is crucial for it to do its job. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Now, when the temperature goes up, this distorts those forces and it disrupts the folding, so that many proteins become non-functional (which is very bad for the cell or organism). The job of <a href="http://pdbj.org/eprots/index_en.cgi?PDB%3A3C7N">Hsp90 and other heat shock proteins</a> is to help them to fold into the right shape – it (almost literally) grabs hold of them and shakes them up and gives them a chance to make the right structure. </span></div><div class="separator" style="clear: both; text-align: center;"><a href="http://pdbj.org/eprots/index_en.cgi?PDB%3A3C7N" style="margin-left: 1em; margin-right: 1em;"><img alt="http://pdbj.org/eprots/index_en.cgi?PDB%3A3C7N" border="0" height="282" src="https://4.bp.blogspot.com/-aQIrTcFpLvU/Vu1-EEYMaxI/AAAAAAAAAvY/xMPwC7YTzVg5q35532QO6Ml9NuPRtDrew/s400/Hsp90.png" width="400" /></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">So, Hsp90 can help a cell deal with sudden stress by detecting and correcting wrongly folded proteins. But the other thing that can make a protein fold wrong is if it has a mutation in it. If you mutate the DNA sequence of a gene you can change the instructions so the wrong amino acid is inserted into the protein at a particular position and that can stop it from folding properly. But if it’s given a good shake by Hsp90, then it can snap out of it and pull itself together.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">That sounds great – Hsp90 can protect the cell from the effects of mutations that alter protein folding. But there’s a dark side – the result is that those kinds of mutations then start to accumulate in a species, because Hsp90 is there to make sure they don’t have any effect. Indeed, all of us have mutations in all kinds of genes that aren’t having any effect because of Hsp90 and genes like it. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Now, do you see where I’m going? What happens when Hsp90 gets mutated? Suddenly all those other mutations – whichever ones were in the background in any particular individual – can have an effect. And that’s exactly what people saw when they <a href="http://www.ncbi.nlm.nih.gov/pubmed/9845070">mutated the Hsp90 in fruitflies</a> – they started seeing flies with all kinds of different phenotypes: deformed or missing eyes, misshapen wings, altered pigmentation, extra bristles, duplicated body parts. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">All kinds of freaky stuff, just from mutating that one gene – all the genetic variation that was being buffered and not having any effect was suddenly released. And not only that, when they put the animals under stressful conditions (high temperature) it got even freakier. Which is another central part of the X-Men mythology – the idea that, while they are born mutants, their abilities often lie latent for years and only come out at times of high stress. Often this is when they’re teenagers, because, as well know, being a teenager is, like, OMG, sooooo stressful!</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">In evolution, this kind of mechanism is hugely important – it allows so-called “<a href="http://www.ncbi.nlm.nih.gov/pubmed/15372091">cryptic genetic variation</a>” to accumulate in a population without affecting the phenotypes of the individuals. But if the environment changes (or the organisms move to a new environment), the stresses associated with that may “release” some of that genetic variation, so that it <a href="http://www.ncbi.nlm.nih.gov/pubmed/17917872">starts to affect the traits of individuals</a>. And somewhere among that pool there may be some changes that are adaptive to the new environment. Those differences may be selected for in the new environment so that the species (though not all the individuals in it) can adapt more rapidly than they would have if they came in with a clean slate, as it were, and had to wait for new mutations to arise. The cryptic genetic variation is thus a <a href="https://en.wikipedia.org/wiki/Evolutionary_capacitance">source of evolutionary potential</a>.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">So, despite the fact that Stan Lee seems to have known very little about genetics, the central premise of the X-Men isn’t that far-fetched after all and actually reflects a mechanism that is central to how species evolve and adapt to new conditions. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Still doesn’t mean we’ll have laser-beams shooting out of our eyeballs any time soon, though…</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2016/03/the-surprising-real-genetics-behind-x.htmlnoreply@blogger.com (Kevin Mitchell)0tag:blogger.com,1999:blog-6146376483374589779.post-1847248271253906846Mon, 04 Jan 2016 15:10:00 +00002016-01-04T07:10:42.307-08:00Sex on the brain – a tale of two studies<div dir="ltr" style="text-align: left;" trbidi="on"><style><!-- /* Font Definitions */ @font-face {font-family:Times; panose-1:2 0 5 0 0 0 0 0 0 0; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} h1 {mso-style-priority:9; mso-style-unhide:no; mso-style-qformat:yes; mso-style-link:"Heading 1 Char"; mso-margin-top-alt:auto; margin-right:0in; mso-margin-bottom-alt:auto; margin-left:0in; mso-pagination:widow-orphan; mso-outline-level:1; font-size:24.0pt; font-family:Times; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; font-weight:bold;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} p {mso-style-noshow:yes; mso-style-priority:99; mso-margin-top-alt:auto; margin-right:0in; mso-margin-bottom-alt:auto; margin-left:0in; mso-pagination:widow-orphan; font-size:10.0pt; font-family:Times; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-bidi-font-family:"Times New Roman";} span.Heading1Char {mso-style-name:"Heading 1 Char"; mso-style-priority:9; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:"Heading 1"; mso-ansi-font-size:24.0pt; mso-bidi-font-size:24.0pt; font-family:Times; mso-ascii-font-family:Times; mso-hansi-font-family:Times; mso-font-kerning:18.0pt; mso-ansi-language:EN-US; font-weight:bold;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style></div>--&gt; <div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><b><span lang="EN-GB"></span></b><span lang="EN-GB">The issue of whether there are biological differences between male and female brains is a fraught one and an area where political positions or prior expectations seem to have a strong influence on the interpretation of scientific data. These trends are illustrated by two papers published in the last couple years, which, despite fairly comparable findings, were interpreted in almost polar opposite fashions. </span></span></span> </div><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">Both studies found strong group differences between male and female brains, one in volume of brain areas, the other in structural connectivity. But the authors of one study went on to (over)interpret these group differences as the basis for sex differences in cognition, while the other downplayed them entirely and instead emphasised the inherent variability within genders to conclude that there was no such thing as a “male brain” or a “female brain”.&nbsp; Both received extensive coverage in the media, fuelled by the associated press releases, resulting in headlines making hilariously contradictory claims, even in the same newspaper!&nbsp;</span></span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">The 2013 study was described with these headlines: </span></span></span></div><br /><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><a href="http://www.uphs.upenn.edu/news/news_releases/2013/12/verma/">Brain Connectivity Study Reveals Striking Differences Between Men and Women</a> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB"><br /></span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB"></span><a href="http://www.independent.co.uk/life-style/the-hardwired-difference-between-male-and-female-brains-could-explain-why-men-are-better-at-map-8978248.html">The hardwired difference between male and female brains could explain why men are 'better at map reading'</a></span></span> </div><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><a href="http://brainblogger.com/2015/01/13/mars-vs-venus-differences-in-male-and-female-brains/"><span lang="EN-GB"><br /></span></a></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><a href="http://brainblogger.com/2015/01/13/mars-vs-venus-differences-in-male-and-female-brains/"> </a></span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><a href="http://brainblogger.com/2015/01/13/mars-vs-venus-differences-in-male-and-female-brains/">Mars Vs Venus – Differences in Male and Female Brains</a></span></span> </div><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB"><br /></span></span></span></div><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><a href="http://www.theguardian.com/science/2013/dec/02/men-women-brains-wired-differently">Male and female brains wired differently, scans reveal</a> (The Guardian)</span></span></div><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">The 2015 study with these:</span></span></span></div><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB"><br /></span></span></span></div><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB"><a href="http://mentalfloss.com/article/71811/there-no-difference-between-male-and-female-brains-study-finds">There Is No Difference Between Male and Female Brains, Study Finds</a></span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> &nbsp;</span></span><br /><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><a href="http://news.sciencemag.org/brain-behavior/2015/11/brains-men-and-women-aren-t-really-different-study-finds">The brains of men and women aren’t really that different, study finds</a></span></span><br /><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"></span></span><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><br /></span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><a href="http://www.statnews.com/2015/11/30/brain-male-female-study/"><span lang="EN-GB">There’s no such thing as a male or female brain, study finds</span></a><span lang="EN-GB"><a href="http://www.statnews.com/2015/11/30/brain-male-female-study/"> </a></span></span></span></div><br /><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span style="font-weight: normal;"><a href="http://www.theguardian.com/science/2015/nov/30/brain-sex-men-from-mars-women-venus-not-so-says-new-study">Men are from Mars, women are from Venus? New brain study says not</a> (The Guardian again!)</span></span></span><br /><br /><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span style="font-weight: normal;">&nbsp;</span> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB"><a href="http://www.theguardian.com/science/2015/nov/30/brain-sex-men-from-mars-women-venus-not-so-says-new-study"></a></span><span lang="EN-GB">Let’s look at the <a href="http://www.pnas.org/content/112/50/15468.abstract">more recent one</a> first, to see what the data actually show and how they were analysed and interpreted. Daphna Joel and colleagues analysed MRI scans of 169 females and 112 males, and segmented them into 116 regions using a standard brain atlas. By analysing how much warping was required to map each brain onto a reference template, it was possible to compare the relative grey matter volume of all these regions across the two sexes. From this group comparison the 10 regions showing the largest sex differences were chosen for subsequent analyses. </span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">So far, so good: the primary finding is that there are statistically significant <i>group differences </i>between males and females in grey matter volume across many brain regions. That’s nothing new – a recent <a href="http://www.ncbi.nlm.nih.gov/pubmed/24374381">meta-analysis</a> of 167 studies confirms consistent group sex differences in many brain areas between men and women </span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">The authors went on, however, to ask what could have been a more interesting question: across those 10 regions, how “male” or “female” were the structures of individual brains? This is where the subjectivity comes in – there are many ways to analyse these data and the authors chose arguably the most simplistic and extreme one, which enabled them to draw the conclusion that male and female brains are not categorically different.&nbsp;</span></span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">They report that: “</span><i>35% percent of brains showed substantial variability, and only 6% of brains were internally consistent</i>”. Importantly they chose to classify only those subjects showing extreme male or female values for <b><i>all 10 regions</i></b> as “internally consistent”. A quick look at panel E of the figure below shows that while such brains may indeed be rare, most of the female brains showed a mostly female pattern (lots of pink) while most of the male brains showed a mostly male pattern (lots of blue – don’t blame me, I didn’t pick the colours!).&nbsp;</span></span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><a href="http://1.bp.blogspot.com/-T85qALGd2F0/VoqE_mtzHWI/AAAAAAAAAuE/8MfBPQ-uXF4/s1600/Joel-15-figure.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="400" src="http://1.bp.blogspot.com/-T85qALGd2F0/VoqE_mtzHWI/AAAAAAAAAuE/8MfBPQ-uXF4/s400/Joel-15-figure.png" width="391" /></a></span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">There is, in fact, nothing at all surprising in their finding of substantial variability within individuals. To explain why, consider the distributions for height for males and females. </span></span></span></div><div class="separator" style="clear: both; text-align: center;"><span style="font-size: small;"><a href="http://3.bp.blogspot.com/-IHvXQHZE07A/VoqFXEHisHI/AAAAAAAAAuM/UBGxcsFjaFs/s1600/height%2Bsex%2Bdiff.jpg" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img border="0" height="213" src="http://3.bp.blogspot.com/-IHvXQHZE07A/VoqFXEHisHI/AAAAAAAAAuM/UBGxcsFjaFs/s320/height%2Bsex%2Bdiff.jpg" width="320" /></a></span></div><span style="font-size: small;">These <a href="http://www.usablestats.com/lessons/normal">distributions</a> are very wide and mostly overlapping but there is a strong and consistent group difference in the mean – the distribution for males is shifted to the right. For any individual, however, knowing their sex gives almost no predictive power for how tall they are. What the group difference does suggest is the following: if I know how tall a particular woman is, I can say that if she had been a man (but was genetically otherwise identical) she would probably have been a little taller than that. She may happen to fall at the low or high end of the overall spectrum <i>for other reasons, </i>but that prediction remains the same. The existence of the group difference does not suggest that all males should be at the extreme “male” end of the height distribution or they’re not really very manly at all. That would be true <i>if all other things were equal</i>, but they’re not equal, and those other variations, which have nothing to do with sex, have a much bigger effect on final height than the sex effect does. </span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">Now, consider what will happen if we have ten different variables, each showing that same sort of wide distribution with an even smaller group sex effect. If the volumes of different brain regions vary independently within individuals (taking overall brain volume out of the equation - as shown <a href="http://www.ncbi.nlm.nih.gov/pubmed/26551545">here</a>, for example), then we should expect some of these values to fall more towards the male end and others more towards the female end in any individual simply due to that underlying variation, which has nothing to do with sex. It would be extremely unlikely to end up at the extreme end for all ten regions, by chance, and such individuals should thus be extremely rare, as observed.</span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">So, the fact that each individual shows this kind of pattern does not mean that each of us has a “mosaic brain” that is partly male and partly female, as claimed by the authors. It is simply exactly what is expected given that sex is only one of the factors affecting the size of each of these regions. We can’t know for each individual what the size of each region <i>would have been</i> if their sex were different (which is really what we’d like to know) – we can only deduce from the group average effects that there would likely have been some effect.</span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">The headlines suggesting that male and female brains are not that different are thus not well supported by these findings at all. The group differences are clear and highly significant. And even if very few of the males or females are at the extreme end of the distribution for <i>all ten</i> of these regions, the overall pattern suggests that you could build a very good classifier from the volumes of these ten regions taken together, which would be quite successful at predicting whether a given brain scan came from a male or a female. Indeed, this would have been a far more objective test of whether MRI volumetric differences between male and female brains are categorical or dimensional.</span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">Given this, it is interesting to ask why the authors chose to analyse and present their data in the way they did. This is what they say in the introduction to the paper:</span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: x-small;"><span style="font-family: Verdana,sans-serif;">"Documented sex/gender* differences in the brain are often taken as support of a sexually dimorphic view of human brains (<b>“</b>female brain<b>” </b>vs. <b>“</b>male brain<b>”</b>), and consequently, of a sexually dimorphic view of human behavior, cognition, personality, attitudes, and other gender characteristics (3). Joel (4, 5) has recently argued that the existence of sex/gender differences in the brain is not sufficient to conclude that human brains belong to two distinct categories. Rather, such a distinction requires the fulfillment of two conditions: one, the form of the elements that show sex/gender differences should be dimorphic, that is, with little overlap between the forms of the elements in males and females. Two, there should be a high degree of internal consistency in the form of the different elements of a single brain (e.g., all elements have the <b>“</b>male<b>” </b>form)."</span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">It seems pretty clear from that that the authors set out to show that male and female brains are not that different, or at least not dimorphic. In particular, they take aim at a <a href="http://www.pnas.org/content/111/2/823.abstract">paper by Madura Ingalhalikar</a> and colleagues (their reference 3, above), which is the second paper I wish to discuss. <span class="MsoHyperlink"></span>These authors found comparable group difference results as Joel et al (using a different measure of brain structure), yet reached almost opposite conclusions. </span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">They used <a href="https://en.wikipedia.org/wiki/Diffusion_MRI">diffusion tensor imaging</a>to define the structural connectivity networks across the brains of 949 youths (428 males and 521 females). They then analysed these networks using a variety of statistical measures of regional and global connectivity and compared these between males and females. They found that females had greater connectivity between hemispheres than males, on average, while males had greater connectivity within each hemisphere. Males also showed greater local connectivity and concomitantly increased modularity in the network (again, on average). </span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><a href="http://3.bp.blogspot.com/-eSVHRb6MIQc/VoqGID1se9I/AAAAAAAAAuY/gOLJfgwI7zE/s1600/Ingalhalikar-13-figure.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="320" src="http://3.bp.blogspot.com/-eSVHRb6MIQc/VoqGID1se9I/AAAAAAAAAuY/gOLJfgwI7zE/s320/Ingalhalikar-13-figure.png" width="310" /></a></span></span></div><br /><div class="MsoNormal"><br /></div><br /><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">(In this figure from the paper, the top panel shows connections that are stronger in males, the bottom those that are stronger in females; blue are intrahemispheric, orange are interhemispheric). </span></span></span></div><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">Once again, so far, so good – the results look significant and interesting. (It would have been nice to see the analyses done with a discovery and replication sample, instead of one big group but at least it is a large sample). Where these authors got onto shakier ground was in extrapolating their findings as explanations for a variety of group differences in cognition between men and women. The participants in the structural connectivity analysis were part of a larger sample for which <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295891/">cognitive data</a> had already been obtained, showing sex differences in a variety of domains. Such differences have been widely documented and range from quite small to fairly large (see here for a <a href="http://www.ncbi.nlm.nih.gov/pubmed/23808917">meta-analysis</a>).&nbsp; </span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">However, the idea that the structural connectivity network differences observed are <i>the cause</i> of such cognitive differences is entirely speculative. I have nothing against speculation, per se, and the discussion section of a paper is a perfect place to explore the possible implications of one’s results. Where this got a bit out of hand was in the associated press release and the consequent media coverage. This is from the <a href="http://www.uphs.upenn.edu/news/news_releases/2013/12/verma/">press release</a> itself:&nbsp;</span></span></span></div><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><span style="font-size: x-small;"><span style="font-family: Verdana,sans-serif;">"“These maps show us a stark difference--and complementarity--in the architecture of the human brain that helps provide a potential neural basis as to why men excel at certain tasks, and women at others,” said Verma. [Regini Verma, senior author]</span></span><br /><br /><span style="font-size: x-small;"><span style="font-family: Verdana,sans-serif;"> </span></span><span style="font-size: x-small;"><span style="font-family: Verdana,sans-serif;">For instance, on average, men are more likely better at learning and performing a single task at hand, like cycling or navigating directions, whereas women have superior memory and social cognition skills, making them more equipped for multitasking and creating solutions that work for a group. They have a mentalistic approach, so to speak. "</span></span><br /><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;">&nbsp; </span></span><br /><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">Those kinds of assertive generalisations, and especially the idea that the connectivity findings provide a neural basis for them, are not at all supported by the data and rightly provoked howls of protest from the scientific community. This included commentary by <a href="http://www.ncbi.nlm.nih.gov/pubmed/24477693">Joel and colleagues</a> , to which <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=24672815">Ingalhalikar and colleagues</a> responded.&nbsp; The unfortunate outcome was that the authors’ over-extrapolation ended up undermining trust in their primary findings, which actually look quite solid in themselves.</span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">To my mind, both these studies over-reached in the interpretation of their results, ironically drawing opposite conclusions from what are broadly comparable primary findings. More generally, it also seems that a little more humility is in order in drawing sweeping conclusions from these kinds of studies, given the crudeness of group-wise volumetric and tractography analyses and the very low resolution of MRI scans. Even if such scans showed no consistent group differences between male and female brains, this would not imply that male and female brains are not different. It would only imply such differences could not be detected by MRI. We know there are many differences in the numbers of neurons in small brain regions or numbers of connections between regions in male and female brains that are invisible to MRI, not to mention sex differences in densities of synaptic spines or other subcellular parameters that have also been demonstrated (as in this recent <a href="http://www.ncbi.nlm.nih.gov/pubmed/26269634">example</a>).&nbsp; </span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">A final note: why should we care? Why should we investigate sex differences in the brain? And if we find them, what are their implications for public policies? Many people are rightly concerned that demonstrations of biological differences in brain structure between males and females will be used to reinforce the idea of systematic differences in cognitive abilities and justify sexism. Of course, even if such differences were large and consistent across individuals, it would not imply one version is better than the other. But more importantly, the distributions for cognitive domains are so overlapping and the sex effects typically so small that inferring anything about the cognitive profiles of individuals on the basis of these group differences is, simply put, a very bad bet. Sex differences for <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=19883140">interests</a> are a little bit bigger, but still by no means categorical and there is likely a strong cultural reinforcement of gender norms in this area.</span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">There are, however, other areas where there are more robust sex differences. The most obvious but also the most commonly over-looked of these is <a href="http://www.wiringthebrain.com/2014/03/gay-genes-yeah-but-no-well-kind-of-but.html">sexual preference</a> – something in the brains of males makes the vast majority of them sexually attracted to females, and vice versa. This is by far the strongest genetic effect on behaviour that we know of in humans (mediated by the <a href="https://en.wikipedia.org/wiki/Testis_determining_factor">SRY</a> gene on the Y chromosome). It would therefore be interesting to find out how that preference is wired into the brain, as an exemplar for how genes can influence innate behaviour. Sex differences in physical aggression are also large and another important topic to understand (as are differences in <a href="http://www.bmj.com/content/349/bmj.g7094">idiotic behaviour</a> as measured by the Darwin awards!).</span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">Finally, though, a main reason we should care is due to the large <a href="http://www.ncbi.nlm.nih.gov/pubmed/20889965">sex differences in prevalence of psychiatric conditions</a>, which range from autism, ADHD and Tourette syndrome (much more common in males), to schizophrenia and dyslexia (more common in males), to depression (more common in females) and eating disorders (much more common in females). There is strong and consistent evidence, for example, that <a href="http://www.ncbi.nlm.nih.gov/pubmed/24581740">females are somewhat protected</a> against the effects of mutations that typically cause autism in males. Females may carry such mutations with relatively little clinical effect; conversely, females who do have autistic symptoms tend to have larger or more severe mutations than affected males (suggesting that it takes a more drastic insult at the genetic level to push a female brain into a clinically autistic state). Understanding how sex influences vulnerability to these conditions is thus a hugely important question. </span></span></span></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span><br /><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"><span lang="EN-GB">Too important to let politics, bias or spin affect our interpretation of scientific findings.&nbsp;</span></span></span></div><div class="MsoNormal"><br /></div><span style="font-size: small;"><span style="font-family: Verdana,sans-serif;"> </span></span>http://www.wiringthebrain.com/2016/01/sex-on-brain-tale-of-two-studies.htmlnoreply@blogger.com (Kevin Mitchell)3tag:blogger.com,1999:blog-6146376483374589779.post-5812617226713688707Thu, 03 Dec 2015 19:47:00 +00002015-12-03T11:47:53.929-08:00autismfalse positivesneuroimagingstatisticsOn literature pollution and cottage-industry science<div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> <br /><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB"></span></b><span lang="EN-GB"></span><span lang="EN-GB">A few days ago there was a minor Twitterstorm over a particular paper that claimed to have found an imaging biomarker that was predictive of some aspect of outcome in adults with autism. The details actually don’t matter that much and I don’t intend to pick on that study in particular, or even link to it, as it’s no worse than many that get published. What it prompted, though, was <a href="http://neurochambers.blogspot.co.uk/2015/11/its-nice-to-nice-but-its-more-important.html?m=1">more interesting</a> – a debate on research practices in the field of cognitive neuroscience and neuroimaging, particularly relating to the size of studies required to address some research questions and the scale of research operation they might entail.</span> </div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">What kicked off the debate was a question of how likely the result they found was to be “real”; i.e., to represent a robust finding that would replicate across future studies and generalise to other samples of autistic patients. I made a fairly uncompromising prediction that it would not replicate, which was based on the fact that the finding derived from: a small sample (n=31, in this case, but split into two), an exploratory study (i.e., not aimed at or constrained by any specific hypothesis, so that group differences in pretty much any imaging parameter would do) and lack of a replication sample (to test directly, with exactly the same methodology, whether the findings from the study were robust, prior to bothering anyone else with them). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The reason for my cynicism is twofold: first, the study was statistically under-powered, and such studies are theoretically more likely to <a href="http://www.ncbi.nlm.nih.gov/pubmed/23571845">generate false positives</a>. Second, and more damningly, there have been literally hundreds of similar studies published using neuroimaging measures to try and identify signatures that would distinguish between groups of people or predict the outcome of illness. For psychiatric conditions like autism or schizophrenia I don’t know of any such “findings” that have held up. We still have no diagnostic or prognostic imaging markers, or any other biomarkers for that matter, that have either yielded robust insights into underlying pathogenic mechanisms or been applicable in the clinic.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There is thus strong empirical evidence that the <i style="mso-bidi-font-style: normal;">small sample, exploratory, no replication </i>design is a sure-fire way of generating findings that are, essentially, <a href="http://www.ncbi.nlm.nih.gov/pubmed/16060722">noise</a>.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This is by no means a problem only for neuroimaging studies; the field of <a href="http://www.huffingtonpost.com/brian-earp/psychology-is-not-in-crisis_b_8077522.html">psychology</a> is grappling with similar problems and many key findings in cell biology have similarly <a href="http://www.ncbi.nlm.nih.gov/pubmed/22460880?dopt=Abstract&amp;holding=npg">failed to replicate</a>. We have seen it before in genetics, too, during the “<a href="http://www.ncbi.nlm.nih.gov/pubmed/16417611">candidate gene</a>era”, when individual research groups could carry out a small-scale study testing single-nucleotide polymorphisms in a particular gene for association with a particular trait or disorder. The problem was the samples were typically small and under-powered, the researchers often tested multiple SNPs, haplotypes or genotypes but rarely corrected for such multiple tests, and they usually did not include a replication sample. What resulted was an entire body of literature hopelessly <a href="http://www.ncbi.nlm.nih.gov/pubmed/20234392">polluted by false positives</a>. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This problem was likely heavily compounded by publication bias, with negative findings far less likely to be published. There is evidence that that problem exists in the neuroimaging literature too, especially for exploratory studies. If you are simply looking for some group difference in any of hundreds or thousands of possible imaging parameters, then finding one may be a (misplaced) cause for celebration, but not finding one is hardly worthy of writing up. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In genetics, the problems with the candidate gene approach were finally realised and fully grappled with. The solution was to perform unbiased tests for SNP associations across the whole genome (<a href="https://en.wikipedia.org/wiki/Genome-wide_association_study">GWAS</a>), to correct rigorously for the multiple tests involved, and to always include a separate replication sample prior to publication. Of course, to enable all that required something else: the formation of enormous consortia to generate the sample sizes required to achieve the necessary statistical power (given how many tests were being performed and the small effect sizes expected). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This brings me back to the reaction on Twitter to the criticism of this particular paper. A number of people suggested that if neuroimaging studies were expected to have larger samples and to also include replication samples, then only very large labs would be able to afford to carry them out. What would the small labs do? How would they keep their graduate students busy and train them? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">I have to say I have absolutely no sympathy for that argument at all, especially when it comes to allocating funding. We don’t have a right to be funded just so we can be busy. If a particular experiment requires a certain sample size to detect an effect size in the expected and reasonable range, then it should not be carried out without such a sample. And if it is an exploratory study, then it should have a replication sample built in from the start – it should not be left to the field to determine whether the finding is real or not. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">You might say, and indeed some people did say, that even if you can’t achieve those goals, because the lab is too small or does not have enough funding, at least doing it on a small scale is better than nothing. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Well, it’s not. It’s worse than nothing. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Such studies just pollute the literature with false positives – obscuring any real signal amongst a mass of surrounding flotsam that future researchers will have to wade through. Sure, they keep people busy, they allow graduate students to be trained (badly), and they generate papers, which often get cited (compounding the pollution). But they are not part of “<a href="https://en.wikipedia.org/wiki/Normal_science">normal science</a>” – they do not contribute incrementally and cumulatively to a body of knowledge. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">We are no further in understanding the neural basis of a condition like autism than we were before the hundreds of small-sample/exploratory-design studies published on the topic. They have not combined to give us any new insights, they don’t build on each other, they don’t constrain each other or allow subsequent research to ask deeper questions. They just sit there as “findings”, but not as facts.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Lest I be accused of being too preachy, I should confess to some of these practices myself. Several years ago, while candidate gene studies were still the norm, we published a <a href="http://www.ncbi.nlm.nih.gov/pubmed/22132072">paper</a> that included a positive association of semaphorin genes with schizophrenia (prompted by relevant phenotypes in mutant mice). It seems quite likely now that that association was a false positive, as a signal from the gene in question has not emerged in larger genome-wide association studies. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">And the one neuroimaging study I have done so far, on synaesthesia, certainly suffered from a small sample size (at the time it was considered decent), and no replication sample. In our defense, <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=24198794">our study</a> was itself designed as a replication of previous findings, combining functional and structural neuroimaging. While our structural findings did mirror those <a href="http://www.wiringthebrain.com/2013/11/popping-hood-on-synaesthesia-whats.html">previously reported</a> (in general direction and spatial distribution of effects, though not precise regions), our functional results were quite incongruent with previous findings. As we did not have a replication sample built into our own design, I can’t be particularly confident that our findings will generalise – perhaps they were a chance finding in a fairly small sample. (Indeed, the imaging findings in synaesthesia have been generally quite <a href="http://www.ncbi.nlm.nih.gov/pubmed/25873873">inconsistent</a> and it is difficult to know which findings constitute real results that future research studies could be built on).</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">If I were designing these kinds of studies now I would use a very different design, with much larger samples and in-built replication (and pre-registration). If that means they are more expensive, so be it. If it means my group can’t do them alone, well that’s just going to be the way it is. No one should fund me, or any lab, to do under-powered studies. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For the neuroimaging field generally that may well mean embracing the idea of larger consortia and adopting common scanning formats that enable <a href="http://www.ncbi.nlm.nih.gov/pubmed/20176931">combining subjects across centres</a>, or at least subsequent meta-analyses. And it will mean that smaller labs may have to give up on the idea of making a living from studies attempting to find differences between groups of people without enough subjects. You’ll find things – they just won’t be real. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2015/12/on-literature-pollution-and-cottage.htmlnoreply@blogger.com (Kevin Mitchell)9tag:blogger.com,1999:blog-6146376483374589779.post-2078039594253788881Sun, 22 Nov 2015 19:16:00 +00002015-11-22T11:16:34.537-08:00common variantsepidemiologygeneticsgenotype-phenotype mappingGWASquantitative traitsrare mutationsSNPsWhat do GWAS signals mean? <div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> <br /><span lang="EN-GB">Genome-wide association studies (<a href="https://en.wikipedia.org/wiki/Genome-wide_association_study">GWAS</a>) have been <a href="http://www.ncbi.nlm.nih.gov/pubmed/22243964">highly successful</a> at linking genetic variation in hundreds of genes to an ever-growing number of traits or diseases. The fact that the genes implicated fit with the known biology for many of these traits or disorders strongly suggests (effectively proves, really) that the findings from GWAS are “real” – they reflect some real biological involvement of those genes in those diseases. (For example, GWAS have implicated skeletal genes in height, immune genes in immune disorders, and neurodevelopmental genes in schizophrenia).</span> <div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">But figuring out the nature of that involvement and the underlying biological mechanisms is much more challenging. In particular, it is not at all straightforward to understand how statistical measures derived at the level of populations relate to effects in individuals. Here, I explore some of the diverse mechanisms in individuals that may underlie GWAS signals.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">GWAS take an <a href="https://en.wikipedia.org/wiki/Epidemiology">epidemiological</a> approach to identify genetic variants associated with risk of disease in exactly the same way epidemiologists identify environmental factors associated with risk – they look for factors that are more frequent in cases with a disease than in unaffected controls. For example, smoking is more common in people with lung cancer than in people without lung cancer (even though only a minority of people who smoke get lung cancer). From this we can deduce that smoking may be a risk-modifying factor for lung cancer, and we can measure the strength of that effect. Of course, observational epidemiology cannot prove causation – but it can provide important clues as to the risk architecture of a disease. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For GWAS, the factors in question are not environmental – they are the differences in our DNA that exist at millions of positions across the genome. These “<a href="https://en.wikipedia.org/wiki/Single-nucleotide_polymorphism">single-nucleotide polymorphisms</a>”, or SNPs, are positions in the genome where the DNA sequence varies between people – sometimes it might be an “A”, sometimes it might be a “T” (or a “G” or a “C”). Of course, any position in the genome can be mutated and likely is mutated in someone on the planet, but such mutations are typically extremely rare. SNPs are different – they are positions where two different versions are both relatively frequent in the population; these versions are thus often referred to as common variants. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">GWAS are premised on the simple idea that if any of those common variants at any of those millions of SNPs across the genome is associated with an increased risk of disease, then that variant should be more frequent in cases than in controls. So, if we find variants that are more common in cases than in controls, we can infer that these variants may be causally related to an increased risk of disease. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">What that doesn’t tell us is how. How does having one variant over another at that particular site cause an increased risk of that particular disease? I don’t just mean by what biological mechanism; I mean how does risk calculated at the population level relate to effects in individuals? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Statistically, we get two measures out of GWAS for any SNP that is associated. One is the p-value, which is a measure of how unlikely it would be to see a frequency difference of the magnitude we observe, just by chance. You might, for example, find that the “A” version at one SNP is at 25% frequency in controls but 28% frequency in cases. That’s not a big difference, so you’d need a very big sample to make sure it wasn’t noise, which is precisely why GWAS now use sample sizes of tens or even hundreds of thousands of people. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">GWAS also apply very rigorous thresholds for statistical significance, in order to <a href="https://en.wikipedia.org/wiki/Multiple_comparisons_problem">correct for</a> the fact that they are testing so many different SNPs. (This follows the logic that, while it is quite unlikely that you will win the lottery yourself, if enough tickets are sold, it won’t be surprising if the lottery is won by somebody). These methods have greatly advanced the trustworthiness of results from the field, far beyond those reported in the benighted “<a href="http://www.in-mind.org/blog/post/where-are-the-genes-for-psychological-traits">candidate gene</a> era”. But the p-value doesn’t tell us anything about how big of an effect there is – how much of an effect on risk does the difference in frequency between cases and controls reflect?</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">That number is summarised by the other measure we get for each associated SNP, which is the <a href="https://en.wikipedia.org/wiki/Odds_ratio">odds ratio</a>. This reflects the <i style="mso-bidi-font-style: normal;">size</i> of the difference in frequency of that variant between cases and controls. It is calculated very simply: say your SNP comes in two versions, or “<a href="https://en.wikipedia.org/wiki/Allele">alleles</a>”: “A” and “G”. We want to convert the difference in absolute frequencies in cases versus controls (say 28% vs 25%, or 62% vs 60%, or whatever it is) into a number that tells us <i style="mso-bidi-font-style: normal;">how many times more common</i> is one version in cases versus controls. (The reason is that that number is more easily related to the increased risk associated with having that version). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Here’s an example: If we take 28% and 25% as frequencies of the “A” allele at a certain SNP in cases and controls, respectively, then if you were to select an “A” allele at random from the sample, the odds of it coming from a case versus a control is 0.28/0.25 (=1.12). The odds of the alternative “G” allele occurring in a case versus a control is correspondingly lower: 0.72/0.75 (=0.96). The odds ratio is then 1.12/0.96 = 1.167. <span style="mso-spacerun: yes;">&nbsp;</span>Assuming that the cases and controls are representative of the general population, we can infer that individuals with an “A” allele are 1.167 times more likely to be a case, compared to those with the “G” allele, which is the number we’re after. (Note that this approximation of odds ratio to <a href="https://en.wikipedia.org/wiki/Relative_risk">relative risk</a> only holds when the disease is rare). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://2.bp.blogspot.com/-WSUMDEzdHYw/VlIS_ld4nLI/AAAAAAAAAts/dF0MUL9y0io/s1600/smoking.jpg" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img border="0" height="213" src="http://2.bp.blogspot.com/-WSUMDEzdHYw/VlIS_ld4nLI/AAAAAAAAAts/dF0MUL9y0io/s320/smoking.jpg" width="320" /></a><span lang="EN-GB">If you do the same calculations for 62% vs 60% it works out to 1.09. These odds ratios are on the order of the typical values obtained from GWAS. For comparison, the odds ratio for smoking and lung cancer is around 30. It is calculated in the same way, e.g., from data like these from a study in Spain in the 1980’s (where smoking was apparently astronomically common!): this study found that 98.8% of lung cancer patients were smokers, while “only” 80.3% of controls were smokers. Doing the same calculations as above gives an OR = 29.1, which is consistent with many other studies.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Thus, for either genetic or environmental factors, the odds ratio gives an average increased risk of disease. But, biologically, what is actually going in each individual that collectively gives that signal? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The most straightforward interpretation is that an odds ratio of, say, 1.2 at the population level reflects exactly the same thing at the individual level – each individual who inherits that SNP variant is at 1.2 times greater risk of developing the disease than they would been otherwise. This is the additive model whereby each SNP acts independently of all other factors – it doesn’t matter what other genetic variants a person has, or indeed what environmental factors they may be exposed to – the added effect on risk of this SNP is the same in all carriers. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">That is, I think, a pretty common interpretation of what the odds ratio means in individuals, but it is certainly not the only scenario that could produce that result at the population level. In the diagram below, I illustrate several different scenarios that could all yield the same odds ratio across the population. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://1.bp.blogspot.com/-KiFVEe_zwNo/VlIO6b6V8KI/AAAAAAAAAtg/zWgVQFXYcR8/s1600/GWAS%2Bsignals-multiple%2Bmeanings.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="365" src="http://1.bp.blogspot.com/-KiFVEe_zwNo/VlIO6b6V8KI/AAAAAAAAAtg/zWgVQFXYcR8/s400/GWAS%2Bsignals-multiple%2Bmeanings.png" width="400" /></a></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-no-proof: yes;"><br /></span><span lang="EN-GB"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The additive scenario is illustrated in A. Every person who inherits the risk allele has a slightly increased risk of disease (small red arrows). [This applies whether the SNP that is genotyped in the GWAS has a functional effect itself or tags another common SNP that is the one doing the damage]. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">It might seem like the odds ratio can be interpreted directly as a multiplier of the baseline risk across the population, i.e., the prevalence of the disease in question. So, if the baseline rate is say 1%, then people with the “A” allele in our example above would have a risk of 1.167%, all other things being equal. The problem with that interpretation is that all other things are not equal. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For example, a condition like autism affects about 1% of the population. This does not mean, however, that everyone in the population had a 1% risk of being born autistic, and that the ones who actually are autistic were just unlucky (statistically speaking, not judgmentally). That 1% is actually made up of people who were at <b style="mso-bidi-font-weight: normal;"><i style="mso-bidi-font-style: normal;">very high risk</i></b> of being autistic – we know this because people with the <a href="http://www.wiringthebrain.com/2014/10/autism-truth-is-not-out-there.html">same genotype as those with autism</a> (i.e., their monozygotic twins) have a rate of autism of over 80%. What this implies is that the vast majority of the population were at effectively <b style="mso-bidi-font-weight: normal;"><i style="mso-bidi-font-style: normal;">no risk</i></b> (not at 1% risk). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This suggests that the effects of any SNP are also likely to be highly unequally distributed across the population*, depending on the genetic background, as illustrated in Scenario B. In some people, the risk variant increases risk a little bit (small red arrows), while in others it increases it a lot (bigger red arrows). In others it may have no effect (flat blue line), while in yet others it may actually decrease risk (green downward arrow). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">That last situation may seem far-fetched but is actually well described; for example, two mutations that each independently cause epilepsy may paradoxically <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=17982453">cancel each other out</a> if they occur together. Similarly, mutations in the fragile X gene, Fmr1, or in the tuberous sclerosis gene, Tsc2, can each cause autism in humans and various neurological and behavioural symptoms when mutated in mice. However, <a href="http://www.nature.com/nature/journal/v480/n7375/full/nature10658.html">combining them both in mice</a>leads to a rescue of the symptoms caused by either one alone (because they counteract each other at the biochemical level). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">These kinds of “<a href="https://en.wikipedia.org/wiki/Epistasis">epistatic</a>” (non-additive) interactions are generally <a href="http://www.wiringthebrain.com/2013/07/no-gene-is-island.html">very common</a> and can be seen for all kinds of complex traits. In terms of how they would contribute to a GWAS signal, a slight preponderance of increased risk when you average those effects across the population would generate a small odds ratio greater than 1. Based on the odds ratio alone, there is no way to distinguish scenarios A and B. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Note that this kind of effect holds for all epidemiological data – the effect sizes obtained are always averages across the population which may hide substantial variability in effect size across individuals. For example, a high-fat diet may be a much higher risk factor for cardiovascular disease in some people than in others, based on their genetic vulnerability. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">It is interesting to note that if those kinds of diverse epistatic interactions occur for each SNP, then their aggregate effects will likely always <a href="http://www.ncbi.nlm.nih.gov/pubmed/18454194">look additive</a>, as these pairwise and higher-order interactions will average out both among and across individuals. That doesn’t mean they could not in principle be <a href="http://www.wiringthebrain.com/2013/07/no-gene-is-island.html">decomposed to reveal such effects</a>, as can be done using various genetic techniques in model organisms. So, just because SNP effects seem to combine additively does not rule out multiple epistatic interactions at the biological level. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Scenario C is a special case of epistatic interaction. In this case, the common risk variant has no effect on biological risk <b style="mso-bidi-font-weight: normal;"><i style="mso-bidi-font-style: normal;">at all</i></b> in most carriers (flat blue lines). However, if it occurs in people with a rare mutation in some specific gene (big purple arrow), which by itself predisposes to the disease with <a href="https://en.wikipedia.org/wiki/Penetrance">incomplete penetrance</a> (where not everyone with the mutation necessarily develops the disease), then it can have a modifying effect, strongly increasing the likelihood of actual expression of the disease symptoms. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Again, this kind of scenario is well documented and is particularly well illustrated by <a href="https://en.wikipedia.org/wiki/Hirschsprung's_disease">Hirschsprung disease</a>. This disorder, which affects innervation of the gut, can be caused by mutations in any one of about 18 known genes, one of which encodes the <a href="https://en.wikipedia.org/wiki/Receptor_tyrosine_kinase#RET_receptor_family">Ret tyrosine kinase</a>. However, mutations in this gene are not completely <a href="https://en.wikipedia.org/wiki/Penetrance">penetrant</a> – some people with it do not develop disease or have only a mild form. <a href="http://www.ncbi.nlm.nih.gov/pubmed/23707863">Recent studies</a> have found that simultaneously carrying a common variant in the same gene increases the likelihood that carriers of the rare mutation will show severe disease. The common variant thus modifies the risk of disease substantially, but only in carriers of a rare mutation. (In this case it is in the same gene, but that doesn’t have to be the case).<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The last scenario, D, is quite different. Here, the common variant is not doing anything itself. It’s not even linked to another common variant that is doing something. Instead, it is linked to a rare mutation that causes disease with much higher penetrance. Or, to put it better, the rare mutation is linked to it. Any new mutation must arise on a background of some set of common SNPs (a “<a href="https://en.wikipedia.org/wiki/Haplotype">haplotype</a>”), with which it will tend to be subsequently co-inherited. If a rare mutation that increases risk of disease rises to an appreciable frequency then it will necessarily increase the frequency of the SNPs in that haplotype in people with the disease, giving rise to what has been called a “<a href="http://www.ncbi.nlm.nih.gov/pubmed/20126254">synthetic association</a>”. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Any one mutation might be too rare to cause such an effect (especially if it is likely to be selected against precisely because it causes disease), but if you have multiple rare mutations at a given locus, and if they happen to occur by chance more on one haplotype than another, then you could get an aggregate effect that could give a tiny difference in frequency of the sort detected by GWAS. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There are now many documented examples where GWAS signals are explained by synthetic associations with rare mutations in the sample, which have much larger odds ratios (e.g., <a href="http://www.ncbi.nlm.nih.gov/pubmed/24550738">1</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/23990791">2</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/23261300">3</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=22968135">4</a>). On the other hand, there are also cases where no such rare mutations have been found (e.g., <a href="http://www.ncbi.nlm.nih.gov/pubmed/23698362">5</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/25275628">6</a>), suggesting that such a mechanism is by no means universal. It is difficult indeed to know how prevalent that situation will turn out to be, though large-scale whole-genome sequencing studies currently underway should help address this question. (See here for theoretical discussions: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20126254">7</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/22792059">8</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/21267061">9</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/21267066">10</a>). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Both scenarios C and D are congruent with the repeated finding that many of the genes implicated by GWAS (with small effect sizes) are known to sometimes carry rare mutations linked to a high risk of the same disease. That would fit with a mechanism whereby common variants at a given locus increase the penetrance of rare mutations in the same gene, but have little effect otherwise (scenario C). Or it would fit with GWAS signals actually arising from synthetic association with high-penetrance rare mutations in the population (where the common variant tags these haplotypes but has no effect itself whatsoever; scenario D). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Teasing these various scenarios apart is a challenge, especially as, for any given disease, different scenarios may pertain for different SNPs. One method has been to try and find a functional effect of a common SNP at the molecular level. For example, SNPs may affect the expression of a gene, altering binding of regulatory proteins to the parts of DNA that specify how much of the protein to make, in which cells and under which conditions. Multiple such examples<a href="http://www.ncbi.nlm.nih.gov/pubmed/24661571"> have been documented</a> (sometimes with surprising results, as when the gene thus affected is actually <a href="http://www.ncbi.nlm.nih.gov/pubmed/24646999">quite distant</a> to the SNP itself). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">However, finding some effect of a common SNP on expression of a gene at a molecular level does not explain how it affects disease risk. Any of scenarios A, B or C could still pertain, and even scenario D is not ruled out by such findings. Indeed, it is not even clear what kind of molecular-level effect we should expect to explain a tiny odds ratio. Should we expect a small effect at the molecular level, or a big effect at the molecular level that translates to a small effect at the organismal level? Or a big effect at the organismal level, but only in combination with other genetic or environmental insults? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">That leaves something of a Catch-22 situation for researchers looking for functional effects of SNPs at the biological level – too small an effect and it will never be detected in messy biological experiments; too big and it will have a rather glaring discrepancy with the epidemiological odds ratio. In the end, it may prove impossible to definitively investigate such small individual epidemiological effects at the biological level, whether from genetic or environmental factors. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This doesn’t mean individual GWAS signals are not useful, of course – they certainly point to loci of interest for further study and have successfully implicated previously unknown biochemical pathways in various diseases (e.g., autophagy in Crohn’s disease). It does mean, however, that the interpretation of individual SNP associations may remain a bit vague. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">On the other hand, while the biological effect of any single SNP in isolation may be small, their <i style="mso-bidi-font-style: normal;">aggregate effect</i> should be large, at least if the model of disease being cause by a polygenic load of such common risk alleles is correct. Indeed, even if the burden of common alleles is not by itself sufficient to cause disease (e.g., in a scenario where they act collectively as a polygenic modifier of rare mutations, which I consider the <a href="http://www.genomebiology.com/2012/13/1/237">most likely scenario</a>), they may still have biological effects in aggregate on relevant traits. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There is now an ever-growing number of studies taking that approach, correlating polygenic scores of risk for various diseases (based on aggregate SNP burden) with a range of biological phenotypes. Whether this approach will really help reveal underlying pathogenic mechanisms remains to be seen. More on that in a later post. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">With thanks to John McGrath for helpful comments and edits. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">*The <a href="http://www.ncbi.nlm.nih.gov/pubmed/25223781">usual way</a> around this is to model the effects of a SNP on the liability scale, rather than the observed scale of risk. This is based on the idea that underlying the observed discontinuous distribution of a disease is a <a href="http://www.genomebiology.com/2012/13/1/237">normally distributed burden of liability</a>, which effectively remains latent until some threshold of burden is passed, in which case disease results. As a mathematical model to describe risk across the population this works reasonably well, given a host of assumptions. It is a mistake, however, in my mind, to think that the model reflects pathogenic mechanisms in individuals. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2015/11/what-do-gwas-signals-mean.htmlnoreply@blogger.com (Kevin Mitchell)1tag:blogger.com,1999:blog-6146376483374589779.post-1854600859673250988Tue, 28 Jul 2015 19:12:00 +00002015-07-28T12:12:51.425-07:00ADHDanimal modelsautismclinical geneticsepilepsyfragile Xgenetic diagnosisintellectual disabilityneurodevelopmental disorderrare disordersschizophreniatherapiesThe Genetics of Neurodevelopmental Disorders <div dir="ltr" style="text-align: left;" trbidi="on"> <span style="font-family: Arial,Helvetica,sans-serif;"><a href="http://4.bp.blogspot.com/-EFj15vzI3Qw/VbfP06jGY2I/AAAAAAAAAs4/VgHji2aEhC4/s1600/Screen%2BShot%2B2015-07-28%2Bat%2B7.53.34%2BPM.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" height="320" src="http://4.bp.blogspot.com/-EFj15vzI3Qw/VbfP06jGY2I/AAAAAAAAAs4/VgHji2aEhC4/s320/Screen%2BShot%2B2015-07-28%2Bat%2B7.53.34%2BPM.png" width="217" /></a><b>The Genetics of Neurodevelopmental Disorders</b> is a new book that will be published by <a href="http://eu.wiley.com/WileyCDA/WileyTitle/productCd-1118524888.html">Wiley</a> in 2015. It is due out in August (in Europe) and September (in the USA), and is available on Amazon <a href="http://www.amazon.com/The-Genetics-Neurodevelopmental-Disorders-Mitchell/dp/1118524888">here</a>.&nbsp;</span><style>@font-face { font-family: "Arial"; }@font-face { font-family: "ＭＳ 明朝"; }@font-face { font-family: "ＭＳ 明朝"; }@font-face { font-family: "Cambria"; }p.MsoNormal, li.MsoNormal, div.MsoNormal { margin: 0in 0in 0.0001pt; font-size: 12pt; font-family: Cambria; }p.MsoFootnoteText, li.MsoFootnoteText, div.MsoFootnoteText { margin: 0in 0in 0.0001pt; font-size: 12pt; font-family: Cambria; }span.MsoFootnoteReference { vertical-align: super; }span.FootnoteTextChar { }.MsoChpDefault { font-family: Cambria; }div.WordSection1 { page: WordSection1; }</style><br /><br /><span style="font-family: Arial,Helvetica,sans-serif;">I had the pleasure of editing the book, which comprises 14 chapters from world-leading scientists and clinicians. Our aim is to provide a timely synthesis of this fast-moving field where so much exciting progress has been made in recent years. Below I have reproduced the Foreword from the book, which outlines the rationale for writing it and the conceptual principles on which it is based, as well as a summary of the topics covered (giving an overview of the state of the field in the process). There are also links to two chapters that are freely available. On behalf of all the authors, I hope the book will prove useful.</span><br /><span style="font-family: Arial,Helvetica,sans-serif;"><br /></span><span style="font-family: Arial,Helvetica,sans-serif;"><br /></span><span style="font-family: Arial,Helvetica,sans-serif;">Foreword</span><br /><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;"></span>&nbsp;</span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">The term “neurodevelopmental disorders” is clinically defined in psychiatry as “</span><i style="mso-bidi-font-style: normal;"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">a group of conditions with onset in the developmental period… characterized by developmental deficits that produce impairments of personal, social, academic, or occupational functioning</span></i><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">” [<a href="http://dsm.psychiatryonline.org/doi/book/10.1176/appi.books.9780890425596">DSM-5</a>]. This term encompasses the clinical categories of intellectual disability (ID), developmental delay (DD), autism spectrum disorders (ASD), attention-deficit hyperactivity disorder (ADHD), speech and language disorders, specific learning disorders, tic disorders and others. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">However, the term can be defined differently, not based on age of onset or clinical presentation, but by an etiological criterion, to mean disorders arising from aberrant neural development. This definition includes many forms of epilepsy (considered either as a distinct disorder or as a co-morbid symptom) as well as disorders like schizophrenia (SZ), which have later onset but which can still be traced back to neurodevelopmental origins. Though the symptoms of SZ itself typically arise only in late teens or early twenties, convergent evidence of epidemiological risk factors during fetal development and very early deficits apparent in longitudinal studies strongly indicate that SZ is a disorder of neural development, though its clinical consequences may remain latent for many years. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Collectively, severe neurodevelopmental disorders affect ~5% of the population (though exact numbers are almost impossible to obtain, due to changing diagnostic criteria and substantial co-morbidity between clinical categories). These disorders impact on the most fundamental aspects of human experience: cognition, language, social interaction, </span>perception, mood, motor control, sense of self. <span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">They impair function, often severely, and restrict opportunities for sufferers, as well as placing a heavy burden on families and caregivers. As lifelong illnesses, they also give rise to a substantial economic burden, both in direct healthcare costs and indirect costs due to lost opportunity. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">The treatments currently available for neurodevelopmental disorders are very limited and problematic. Intensive educational interventions may help ameliorate some cognitive or behavioural difficulties, such as those associated with ID or ASD, but to a limited extent and without addressing the underlying pathology. With respect to psychiatric symptoms, th</span><span lang="EN-GB">e mainstays of pharmacotherapy (antipsychotic medication, mood stabilizers, antidepressants and anxiolytics) all emerged between the 1940’s and 1960’s with almost no new drugs being developed since. Most of these treatments were discovered serendipitously, and their mechanisms of action remain poorly understood. In most cases, the existing treatments are only partially effective and can induce serious side effects. This is also true for the range of anticonvulsants, and, for all these drugs, it is typically impossible to predict from symptom profiles alone whether individual patients will benefit from a particular drug or possibly be harmed by it. These difficulties and the attendant poor outcomes for many patients arise from not knowing the causes of disease in particular patients and not understanding the underlying pathogenic mechanisms. Genetic research promises to address both these issues. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">Neurodevelopmental disorders are predominantly genetic in origin and have often been thought of as falling into two groups. The first includes a very large number of individually rare syndromes with known genetic causes. Examples include Fragile X syndrome, Down syndrome, Rett syndrome and Angelman syndrome but there are literally hundreds of others. Each of these is clearly caused by a single genetic lesion, sometimes involving an entire chromosome or a section of chromosome, sometimes affecting a single gene. Most are characterised by ID, but many also show high rates of epilepsy, ASD or other neuropsychiatric symptoms. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">The second group comprises idiopathic cases of ID, ASD, SZ or epilepsy – those with no currently known cause. Despite the lack of an identified genetic lesion, there is still very strong evidence of a genetic etiology across these categories. All of these conditions are highly heritable, </span><span lang="GA" style="mso-ansi-language: GA;">showing high levels of twin concordance, much higher in monozygotic than in dizygotic twins, substantially increased risk to relatives and typically zero effect of a shared family environment, indicating strong genetic causation. </span><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;"></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">What has not been clear is whether these so-called “common disorders” are simply collections of rare genetic syndromes that we cannot yet discriminate, or whether they have a very different genetic architecture. The dominant paradigm in the field has held that the idiopathic, non-syndromic cases of common disorders like ASD or SZ reflect the extreme end of a continuum of risk across the population. This is based on a model involving the segregation of a very large number of genetic variants, each of small effect alone, which can, above a collective threshold of burden in individuals, result in frank disease. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">Recent genetic discoveries are prompting a re-evaluation of this model, as well as casting doubt on the biological validity of clinical diagnostic categories. After decades of frustration, the genetic secrets of these conditions are finally yielding to new genomic microarray and sequencing technologies. These are revealing a growing list of rare, single mutations that confer high risk of ASD, ID, SZ or epilepsy, particularly epileptic encephalopathies. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">These findings strongly reinforce a model of genetic heterogeneity, whereby common clinical categories do not represent singular biological entities, but rather are umbrella terms for a large number of distinct genetic conditions. These conditions are individually rare but collectively common. Strikingly, almost all of the identified mutations are associated with variable clinical manifestations, conferring risk across traditional diagnostic boundaries. These findings fit with large-scale epidemiological studies that also show shared risk across these disorders. Thus, while current diagnostic categories may reflect more or less distinct clinical states or outcomes, they do not reflect distinct etiologies. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">The “genetics of autism” is thus neither singular nor separable from the “genetics of intellectual disability”, the “genetics of schizophrenia” or the “genetics of epilepsy”. The more general term of “<i style="mso-bidi-font-style: normal;">developmental brain dysfunction</i>” has been proposed to encompass disorders arising from altered neural development, which can manifest clinically in diverse ways. This book is about the genetics of developmental brain dysfunction. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">A lot can go wrong in the development of a human brain. The right numbers of hundreds of distinct types of nerve cells have to be generated in the right places, they have to migrate to form highly organised structures, and they must extend nerve fibres, which navigate their way through the brain to ultimately find and connect with their appropriate partners, avoiding wrong turns and illicit interactions. Once they find their partners they must form synapses, the incredibly complex and diverse cellular structures that mediate communication between nerve cells. These synapses are also highly dynamic, responding to patterns of activity by strengthening or weakening the connection. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">The instructions to carry out these processes are encoded in the genome of the developing embryo. Each of these aspects of neural development requires the concerted action of the protein products of thousands of distinct genes. Mutations in any one of them (or sometimes in several at the same time) can lead to developmental brain dysfunction.</span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">The identification of numerous causal mutations has focused attention on the roles of the genes affected, with a number of prominent classes of neurodevelopmental genes emerging. These include genes involved in early brain patterning and proliferation, those mediating later events of cell migration and axon guidance, and a major class involved in synapse formation and subsequent activity-dependent synaptic refinement, pruning and plasticity. Also highlighted are a number of biochemical pathways and networks that appear especially sensitive to perturbation. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">Genetic discoveries thus allow an alternate means to classify disorders, based on the underlying neurodevelopmental processes affected. This provides more etiologically valid and arguably more biologically coherent categories than those based on clinical outcome. For individual patients, the application of microarray and sequencing technologies is already changing clinical practice in diagnosis and management of neurodevelopmental disorders. This will only increase as more and more pathogenic mutations are identified. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">Such discoveries also provide entry points to enable the elucidation of pathogenic mechanisms, where exciting progress is being made using cellular and animal models. For any given mutation, this involves defining the defects at a cellular level (in the right cells), and working out how such defects propagate to the levels of neural circuits and systems, ultimately producing pathophysiological states that underlie neuropsychiatric symptoms. Definition of these pathways will hopefully lead to a detailed enough understanding of the molecular or circuit-level defects to rationally devise new therapeutics. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">The elucidation of the heterogeneous genetic and neurobiological bases of neurodevelopmental disorders should thus enable a much more personalised approach to diagnosis and treatment for individual patients, and a shift in clinical care for these disorders from an approach based on superficial symptoms and generic medicines, to one based on detailed knowledge of specific causes and mechanisms. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial; mso-font-kerning: 14.0pt;">The book is organised into several sections:</span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial;">Chapters 1-6 cover broad conceptual issues relevant to neurodevelopmental disorders in general. These are informed by recent advances in genomic technologies, which have transformed our view of the genetic architecture of both rare and so-called “common” neurodevelopmental disorders. These chapters will consider the genetic heterogeneity of clinical categories like ASD or SZ, the relative importance of different types of mutations (common vs rare; single-gene vs large deletions or duplications; inherited vs <i style="mso-bidi-font-style: normal;">de novo</i>), etiological overlap between clinical categories and complex interactions between two or more mutations or between genetic and environmental factors.<span style="mso-spacerun: yes;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial;">A preprint of Chapter 1, by me, on <b>The Genetic Architecture of Neurodevelopmental Disorders</b>, is available <a href="http://biorxiv.org/content/early/2014/09/19/009449">here</a>.&nbsp; </span></span></div><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial;">Chapters 7-9 present our current understanding of several different types of disorder, grouped by the neurodevelopmental process impacted. Consideration of disorders from this angle provides a more rational and biologically valid approach than consideration from the point of view of clinical symptoms, which can be arrived at through various routes. </span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial;">Chapters 10-11 deal with the elucidation of pathogenic mechanisms, following genetic discoveries. They include chapters on cellular models (using induced pluripotent stem cells derived from patients) and animal models (recapitulating pathogenic mutations in mice), which are revealing the routes of pathogenesis, from defects in diverse cellular neurodevelopmental processes to resultant alterations in neural circuits and brain systems, which ultimately impinge on behaviour. The manifestation of these defects in humans also depends on processes of learning and experience-dependent development that proceed for many years after birth. Taking this aspect of development seriously is essential as it is a critical period where symptoms can be exacerbated if neglected or potentially improved by intensive interventions.<span style="mso-spacerun: yes;">&nbsp; </span></span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial;">Chapters 13-14 consider the clinical implications of recent discoveries and of the general principles described in earlier chapters. Foremost among these is the recognition of extreme genetic heterogeneity, meaning that understanding what is going on in any particular patient requires knowledge of the specific underlying genetic cause. The dramatic reductions in cost for whole-genome sequencing mean such diagnoses will become far easier to make, with important implications for clinical genetic practice (including preimplantation or prenatal screening or diagnosis). Finally, the study of cellular and animal models of specific disorders is already suggesting potential therapeutic avenues for some conditions. These advances illustrate a general principle – to treat these conditions we need to identify and understand the underlying biology and design therapies to treat the specific cause in each patient and not just the generic symptoms.</span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial;">A preprint of Chapter 13, by Gholson Lyon and Jason O'Rawe, on </span><span lang="EN-GB" style="mso-bidi-font-family: Arial;"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:1; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:variable; mso-font-signature:0 0 0 0 0 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> </span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Times New Roman&quot;;">Human genetics and clinical aspects of neurodevelopmental disorders</span></b><span lang="EN-GB" style="mso-bidi-font-family: Arial;"> is available <a href="http://biorxiv.org/content/early/2014/10/06/000687">here</a>.</span></span></div><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial;"><br /></span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="EN-GB" style="mso-bidi-font-family: Arial;">The full Table of Contents is shown below:</span></span></div><div class="MsoNormal"><br /></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span><div style="mso-element: footnote-list;"> <style><!-- /* Font Definitions */ @font-face {font-family:Arial; panose-1:2 11 6 4 2 2 2 2 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:"Courier New"; panose-1:2 7 3 9 2 2 5 2 4 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:新細明體; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:136; mso-generic-font-family:auto; mso-font-format:other; mso-font-pitch:variable; mso-font-signature:1 134742016 16 0 1048576 0;} @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:1; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:variable; mso-font-signature:0 0 0 0 0 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:新細明體; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB; mso-fareast-language:JA;} p.MsoListParagraph, li.MsoListParagraph, div.MsoListParagraph {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; margin-top:0in; margin-right:0in; margin-bottom:10.0pt; margin-left:.5in; mso-add-space:auto; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:新細明體; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-fareast-language:ZH-TW;} p.MsoListParagraphCxSpFirst, li.MsoListParagraphCxSpFirst, div.MsoListParagraphCxSpFirst {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:新細明體; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-fareast-language:ZH-TW;} p.MsoListParagraphCxSpMiddle, li.MsoListParagraphCxSpMiddle, div.MsoListParagraphCxSpMiddle {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:新細明體; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-fareast-language:ZH-TW;} p.MsoListParagraphCxSpLast, li.MsoListParagraphCxSpLast, div.MsoListParagraphCxSpLast {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:10.0pt; margin-left:.5in; mso-add-space:auto; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:新細明體; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-fareast-language:ZH-TW;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:11.0pt; mso-ansi-font-size:11.0pt; mso-bidi-font-size:11.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:新細明體; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-fareast-language:ZH-TW;} .MsoPapDefault {mso-style-type:export-only; margin-bottom:10.0pt; line-height:115%;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} /* List Definitions */ @list l0 {mso-list-id:1329558423; mso-list-type:hybrid; mso-list-template-ids:1807285140 67698703 67698713 67698715 67698703 67698713 67698715 67698703 67698713 67698715;} @list l0:level1 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level2 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level3 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level4 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level5 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level6 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level7 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level8 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level9 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} ol {margin-bottom:0in;} ul {margin-bottom:0in;} --></style><div class="MsoNormal" style="text-indent: .5in;"><span style="font-family: Arial,Helvetica,sans-serif;"><b style="mso-bidi-font-weight: normal;"><span lang="GA" style="mso-ansi-language: GA;">Foreword</span></b><span lang="GA" style="mso-ansi-language: GA;"><br /><span style="mso-tab-count: 1;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span>Kevin J. Mitchell</span></span></div><div class="MsoNormal"><br /></div><div class="MsoListParagraphCxSpFirst" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span lang="GA" style="mso-ansi-language: GA; mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">1.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span lang="GA" style="mso-ansi-language: GA;">The Genetic Architecture of Neurodevelopmental Disorders<br /></span></b><span lang="GA" style="mso-ansi-language: GA;">Kevin J. Mitchell <br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">2.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;">Overlapping Etiology of Neurodevelopmental Disorders<br /></b>Eric Kelleher and Aiden Corvin</span><span style="font-family: Arial,Helvetica,sans-serif;"><br style="mso-special-character: line-break;" /></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">3.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">The Mutational Spectrum of Neurodevelopmental Disorders</span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;"><br />Nancy D. Merner, Patrick A. Dion and Guy A. Rouleau<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">4.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span></b><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">The Role of Genetic Interactions in Neurodevelopmental Disorders</span></b></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Jason H. Moore and Kevin J. Mitchell<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">5.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Developmental Instability, Mutation Load, and Neurodevelopmental Disorders</span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;"><br />Ronald A. Yeo and Steven W. Gangestad<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">6.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Environmental Factors and Gene-Environment Interactions</span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;"><br />John McGrath<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">7.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">The Genetics of Brain Malformations<br /></span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;">M. Chiara Manzini and Christopher A. Walsh<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">8.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Disorders of Axon Guidance<br /></span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Heike Blockus and Alain Ch</span><span style="mso-bidi-font-family: Arial;">é</span><span style="mso-bidi-font-family: &quot;Courier New&quot;;">dotal<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">9.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Synaptic Disorders</span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;"><br />Catalina Betancur and Kevin J. Mitchell<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">10.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Human Stem Cell Models of Neurodevelopmental Disorders</span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;"><br />Peter Kirwan and Frederick J. Livesey<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">11.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Animal Models for Neurodevelopmental Disorders</span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;"><br />Hala Harony-Nicolas and Joseph D. Buxbaum<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">12.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Cascading Genetic and Environmental Effects on Development: Implications for Intervention</span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;"><br />Esha Massand and Annette Karmiloff-Smith<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">13.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Human Genetics and Clinical Aspects of Neurodevelopmental Disorders</span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;"><br />Gholson J. Lyon and Jason O’Rawe<br style="mso-special-character: line-break;" /><br style="mso-special-character: line-break;" /></span></span></div><div class="MsoListParagraphCxSpLast" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-family: Arial,Helvetica,sans-serif;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Calibri; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">14.<span style="font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-size-adjust: none; font-size: 7pt; font-stretch: normal; font-style: normal; font-synthesis: weight style; font-variant: normal; font-weight: normal; line-height: normal;">&nbsp; </span></span></span><b style="mso-bidi-font-weight: normal;"><span style="mso-bidi-font-family: &quot;Courier New&quot;;">Progress Toward Therapies and Interventions for Neurodevelopmental Disorders</span></b><span style="mso-bidi-font-family: &quot;Courier New&quot;;"><br />Ayokunmi Ajetunmobi and Daniela Tropea</span></span></div><span style="font-family: Arial,Helvetica,sans-serif;"><br clear="all" /></span><div id="ftn1" style="mso-element: footnote;"><div class="MsoFootnoteText"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://www.blogger.com/blogger.g?blogID=6146376483374589779#_ftnref1" name="_ftn1" style="mso-footnote-id: ftn1;" title=""><span class="MsoFootnoteReference"><span lang="EN-GB"><span style="mso-special-character: footnote;"><span class="MsoFootnoteReference"><span lang="EN-GB" style="font-size: 12pt;"></span></span></span></span></span></a><span lang="EN-GB"></span><span style="mso-ansi-language: EN-US;"></span></span></div></div></div><span style="font-family: Arial,Helvetica,sans-serif;"> </span></div>http://www.wiringthebrain.com/2015/07/the-genetics-of-neurodevelopmental.htmlnoreply@blogger.com (Kevin Mitchell)0tag:blogger.com,1999:blog-6146376483374589779.post-2936032823901165291Thu, 30 Apr 2015 16:43:00 +00002015-04-30T09:43:16.821-07:00autismclinical geneticscommon disorderscopy number variantsepilepsygenetic diagnosisintellectual disabilityrare disordersrare mutationsschizophreniaGenetics in Modern Medicine – the Future is Now<div dir="ltr" style="text-align: left;" trbidi="on"><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style></div>--&gt; <div class="MsoNormal"><a href="http://www.genengnews.com/gen-articles/turning-data-into-genomic-medicine/3486/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://www.genengnews.com/gen-articles/turning-data-into-genomic-medicine/3486/" border="0" src="http://2.bp.blogspot.com/-DD3zrpO2q6o/VT-5f-a14NI/AAAAAAAAAr8/I5bgrTaL_MI/s1600/Genomic%2Bmedicine.jpg" height="213" width="320" /><span lang="EN-GB"></span></a><span lang="EN-GB"></span><span lang="EN-GB"></span><span lang="EN-GB">The <a href="http://www.genome.gov/10001772">Human Genome Project</a> was founded on the premise that it would unlock the secrets of disease and lead to new cures for many disorders. While the new cures have mostly yet to materialise, the secrets of disease are indeed being revealed, in ways that will transform medicine over the coming years. Both our knowledge of the genetic causes of disease and our ability to test for those causes have increased exponentially in recent years. These advances will place genetic testing at the front line of diagnostics, not just for the relatively small number of already well-known inherited disorders, but for an ever-widening array of conditions, both rare and common.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The lifetime prevalence of rare disorders in European populations is estimated at 6-8% of the population (National <a href="http://health.gov.ie/blog/publications/national-rare-disease-plan-for-ireland-2014-2018/">Rare Disease Plan</a> for Ireland, 2014-2018). Over 6,000 distinct genetic disorders are already defined and more are being discovered at an increasing pace. For many patients with such disorders, their experience with the health system involves a long and frustrating diagnostic odyssey. They are typically seen by various specialists for various symptoms, but the connections between them are not always recognised. A referral for genetic testing may be made eventually, but usually as a last resort rather than a first option. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In a growing proportion of such cases, genetic testing can reveal the underlying cause of the condition, bringing certainty and insight to the diagnosis. While specific medications may not exist that target each condition, a genetic diagnosis can often provide useful predictions of prognosis and treatment responsiveness. This is especially true for the hundreds of <a href="http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html">metabolic disorders</a>, which may be treatable by dietary interventions or supplements. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">But even in cases where there are no direct medical implications, just receiving a specific diagnosis can be highly beneficial in helping patients and their families cope with the situation. In addition, many international support groups have arisen relating to specific disorders, or for rare diseases in general, such as <a href="https://www.rarediseases.org/rare-disease-information/rare-diseases">NORD</a> (U.S.), <a href="http://www.grdo.ie/">GRDO</a> (Ireland) and <a href="http://www.raredisease.org.uk/">Rare Disease UK</a>. These organisations are helping patients, parents and clinicians share information, compare experiences and improve outcomes. Genetic information can also inform future reproductive decisions, including possibilities such as <a href="http://en.wikipedia.org/wiki/Preimplantation_genetic_diagnosis">pre-implantation genetic</a> screening.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Rare mutations can cause common disorders</span></b></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The effects of genetic mutations are not restricted to what we typically think of as rare disorders, however. Discoveries over the last several years are illustrating their central role in much more common disorders, such as epilepsy, autism, schizophrenia, Alzheimer’s and Parkinson’s disease, many cancers and other conditions. Indeed, many of those diagnostic categories may in fact be umbrella terms for a <a href="http://www.wiringthebrain.com/2014/07/common-disorders-are-really-collections.html">multiplicity of rare disorders</a> that manifest with similar symptoms. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For neuropsychiatric conditions, it has long been known that such disorders are highly heritable, but it had not been possible to identify causal genes. That has changed, with the development of new DNA sequencing technologies, yielding insights that overturn our conception of such disorders. Rather than reflecting a single entity, broad clinical categories like autism or epilepsy obscure an extreme diversity of underlying conditions. Each of these conditions may be quite rare but there are so many of them that manifest in similar ways that collectively they result in highly prevalent disorders. Genetics now provides the tools to distinguish them.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The causal mutations in patients with these conditions can disrupt single genes or can delete or duplicate small sections of chromosomes, affecting multiple genes at once. For very severe cases, the mutations will often have arisen <a href="http://www.wiringthebrain.com/2012/04/de-novo-mutations-in-autism.html">de novo</a>, in the generation of egg or, more commonly, sperm cells. But others are inherited, often from parents who are clinically unaffected, despite carrying the mutation. This highlights the complexity in relating genotypes to phenotypes – the clinical presentation of such mutations is quite variable and often depends on other genetic or environmental factors. Nevertheless, in a patient showing symptoms, the <a href="http://www.wiringthebrain.com/2014/01/on-genetic-causality-forwards-and.html">identification of a major mutation</a> can reveal important information as to the primary cause. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For example, for patients with a diagnosis of autism – a diagnosis based on symptoms alone – genetic testing for specific conditions like <a href="http://ghr.nlm.nih.gov/condition/fragile-x-syndrome">Fragile X syndrome</a> or <a href="http://ghr.nlm.nih.gov/condition/rett-syndrome">Rett syndrome</a> has been in place for some time. This is now being expanded to include testing for a growing number of chromosomal disorders or single-gene mutations, which collectively can now explain <a href="http://www.ncbi.nlm.nih.gov/pubmed/20466091">~15% of cases</a> – a huge increase from just a few years ago. This percentage is growing all the time as causal mutations in new genes are identified (reaching <a href="http://www.ncbi.nlm.nih.gov/pubmed/23425232">20-25% in recent studies</a>). The successes for autism are likely to be duplicated for other conditions as the number of sequenced patient genomes increases. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Genome sequencing now an affordable front-line option</span></b></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The pace of technological change in this field is simply staggering. We are moving from a </span></div><div class="separator" style="clear: both; text-align: center;"><a href="https://www.genome.gov/sequencingcosts/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="https://www.genome.gov/sequencingcosts/" border="0" src="http://2.bp.blogspot.com/-wMX3kUDkaWs/VT_M5m6pyoI/AAAAAAAAAsM/6Hc79mrz88c/s1600/sequencing%2Bcosts.jpg" height="240" width="320" /><span id="goog_2062514870"></span></a><span id="goog_2062514871"></span></div>position of being able to test a few specific genes implicated in any particular disorder, to one where it will be cheaper and faster, as well as more informative, to sequence the patient’s entire genome. It took thousands of researchers over ten years to sequence the reference Human Genome, at a total cost of about $3,000,000,000. Today, a human genome <a href="https://www.genome.gov/sequencingcosts/">can be sequenced</a> for under $2,000, in about a day, maybe two. <br /><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Those sequencing costs and times are still falling as new technologies are developed and economies of scale brought to bear. This brings genome sequencing into the cost range of many blood tests, radiological scans, or other investigative procedures and suggests it may soon become a front-line test for many patients with idiopathic disease. Indeed, it may become cheaper for doctors to order a genome sequence than to spend any of their own time wondering about whether to order it. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">But genomic data are only useful if someone can interpret them, a far greater task than simply checking for the presence of a mutation in a specific gene. As it happens, each of us carries a <a href="http://genomesunzipped.org/2012/02/all-genomes-are-dysfunctional-broken-genes-in-healthy-individuals.php">couple hundred mutations</a> in our genome that seriously impact on gene function. Most of these do not cause disease, however, and it is therefore a challenge to <a href="http://www.wiringthebrain.com/2010/10/searching-for-needle-in-needle-stack.html">recognise a pathogenic mutation</a> amongst this background burden of mutations we all carry. That job will be made easier as genetic information becomes available for more and more patients. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">A national strategy for genetic services</span></b></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The enormous potential benefits of such information have been recognised in several countries, most recently in the UK where the NHS has launched a project to sequence <a href="http://www.genomicsengland.co.uk/">100,000 genomes</a>, including those of thousands of patients with diverse disorders. The genetic heritage of each population is different, however, with some pathogenic mutations at much higher frequencies in specific populations, as with mutations causing <a href="https://www.cfireland.ie/">cystic fibrosis</a> in Ireland. Characterising the genetic heritage of the Irish population is thus an important goal as a necessary foundation for clinical genetic testing.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The health and economic benefits of this genetic revolution will only be realised if there is adequate provision and funding of genetic testing and <a href="http://en.wikipedia.org/wiki/Genetic_counseling">genetic counselling</a> services. In Ireland we currently lag far behind most other developed countries in the provision of these services, a situation exacerbated by the recent <a href="http://www.irishtimes.com/news/health/warning-that-national-genetics-centre-proposal-could-lead-to-huge-clinical-risk-1.1998291">decision to downgrade</a>what was the </span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">National Centre for Medical Genetics at Our Lady’s Hospital in Crumlin to a department within the hospital. On the contrary, if the health service in Ireland is to keep pace with international developments and provide the best care for patients, the role of genetics services will have to be greatly expanded in the future.&nbsp;</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">[</span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"><span lang="EN-GB">This piece was written for "The Consultant" - the magazine of the Irish Consultants Association and appears in the Spring 2015 issue. It is reproduced here with their consent.] </span> </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"> </span></div>http://www.wiringthebrain.com/2015/04/genetics-in-modern-medicine-future-is.htmlnoreply@blogger.com (Kevin Mitchell)0tag:blogger.com,1999:blog-6146376483374589779.post-6921050912624681107Mon, 24 Nov 2014 10:01:00 +00002014-11-24T08:09:30.190-08:00agencyconsciousnessdeterminismfree willinformationmaterialismmeaningpurposeTop-down causation and the emergence of agency<div dir="ltr" style="text-align: left;" trbidi="on"><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; mso-themecolor:hyperlink; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} pre {mso-style-priority:99; mso-style-link:"HTML Preformatted Char"; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:Courier; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-bidi-font-family:Courier;} span.HTMLPreformattedChar {mso-style-name:"HTML Preformatted Char"; mso-style-priority:99; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:"HTML Preformatted"; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; font-family:Courier; mso-ascii-font-family:Courier; mso-hansi-font-family:Courier; mso-bidi-font-family:Courier; mso-ansi-language:EN-US;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style> <a href="http://nelsoncosentino.deviantart.com/art/Machine-Brain-2-129467519" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://nelsoncosentino.deviantart.com/art/Machine-Brain-2-129467519" border="0" src="http://3.bp.blogspot.com/-hLgqeag5_XA/VHL-U9UoOJI/AAAAAAAAAps/8cvszmW1qzU/s1600/brain-machine-2.jpg" height="200" width="173" /></a><span lang="EN-GB">There is a paradox at the heart of modern neuroscience. As we succeed in explaining more and more cognitive operations in terms of patterns of electrical activity of specific neural circuits, it seems we move ever farther from bridging the gap between the physical and the mental. Indeed, each advance seems to further relegate mental activity to the status of <a href="http://en.wikipedia.org/wiki/Epiphenomenon">epiphenomenon</a> – something that emerges from the physical activity of the brain but that plays no part in controlling it. It seems difficult to reconcile the reductionist, reverse-engineering approach to brain function with the idea that we human beings have thoughts, desires, goals and beliefs that influence our actions. If actions are driven by the physical flow of ions through networks of neurons, then is there any room or even any need for psychological explanations of behaviour? </span> <br /><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">How vs Why</span></b></div><div class="MsoNormal"><span lang="EN-GB">To me, that depends on what level of explanation is being sought. If you want to understand <i style="mso-bidi-font-style: normal;">how</i> an organism behaves, it is perfectly possible to describe the mechanisms by which it processes sensory inputs, infers a model of the outside world, integrates that information with its current state, weights a variety of options for actions based on past experience and predicted consequences, inhibits all but one of those options, conveys commands to the motor system and executes the action. If you fill in the details of each of those steps, that might seem to be a complete explanation of the causal mechanisms of behaviour. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">If, on the other hand, you want to know <i style="mso-bidi-font-style: normal;">why</i> it behaves a certain way, then an explanation at the level of neural circuits (and ultimately at the level of molecules, atoms and sub-atomic particles) is missing something. It’s missing meaning and purpose. Those are not physical things but they can still have causal power in physical systems. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Why are why questions taboo?</span></b></div><div class="MsoNormal"><a href="http://scienceandreligion472.blogspot.ie/2013/08/aristotle-4-causes-and-substance-versus.html" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://scienceandreligion472.blogspot.ie/2013/08/aristotle-4-causes-and-substance-versus.html" border="0" src="http://4.bp.blogspot.com/-OhKVZB5_Nik/VHL-pCVOJtI/AAAAAAAAAp0/HaE4vHAo7ME/s1600/Aristotles%2Bcauses.jpg" height="200" width="320" /></a><span lang="EN-GB">Aristotle articulated a theory of <a href="http://plato.stanford.edu/entries/aristotle-causality/">causality</a>, which defined four causes or types of explanation for how natural objects or systems (including living organisms) behave. The <i style="mso-bidi-font-style: normal;">material</i> <i style="mso-bidi-font-style: normal;">cause</i> deals with the physical identity of the components of a system – what it is made of. On a more abstract level, the <i style="mso-bidi-font-style: normal;">formal</i> <i style="mso-bidi-font-style: normal;">cause</i> deals with the form or organisation of those components. The <i style="mso-bidi-font-style: normal;">efficient</i> <i style="mso-bidi-font-style: normal;">cause</i> concerns the forces outside the object that induce some change. And – finally – the <i style="mso-bidi-font-style: normal;">final</i> <i style="mso-bidi-font-style: normal;">cause</i> refers to the end or intended purpose of the thing. He saw these as complementary and equally valid perspectives that can be taken to provide explanations of natural phenomena. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">However, Francis Bacon, the father of the scientific method, <a href="http://plato.stanford.edu/entries/francis-bacon/">argued</a> that scientists should concern themselves only with material and efficient causes in nature – also known as matter and motion. Formal and final causes he consigned to Metaphysics, or what he called “magic”! Those attitudes remain prevalent among scientists today, and for good reason – that focus has ensured the phenomenal success of reductionist approaches that study matter and motion and deduce mechanism. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Scientists are trained to be suspicious of “why questions” – indeed, they are usually told explicitly that science cannot answer such questions and shouldn’t try. And for most things in nature, that is an apt admonition – really against <a href="http://en.wikipedia.org/wiki/Anthropomorphism">anthropomorphising</a>, or ascribing human motives to inanimate objects, like single cells or molecules or even to organisms with less complicated nervous systems and, presumably, less sophisticated inner mental lives. Ironically, though, some people seem to think we shouldn’t even anthropomorphise humans!</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Causes of behaviour can be described both at the level of mechanisms and at the level of reasons. There is no conflict between those two levels of explanation nor is one privileged over the other – both are active at the same time. Discussion of meaning does not imply some mystical or supernatural force that over-rides physical causation. It’s not that non-physical stuff pushes physical stuff around in some <a href="http://en.wikipedia.org/wiki/Dualism_%28philosophy_of_mind%29">dualist</a> dance. (After all, “non-physical stuff” is a contradiction in terms). It’s that the higher-order organisation of physical stuff – which has both informational content and <i style="mso-bidi-font-style: normal;">meaning</i> for the organism – constrains and directs how physical stuff moves, because it is <i style="mso-bidi-font-style: normal;">directed towards a purpose</i>.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Purpose is incorporated in artificial things by design – the washing machine that is currently annoying me behaves the way it does because it is designed to do so (though it could probably have been designed to be quieter). I could explain how it works in purely physical terms relating to the activity and interactions of all its components, but the reason it behaves that way would be missing from such a description – the components are arranged the way they are so that the machine can carry out its designed function. In living things, purpose is not designed but is cumulatively incorporated in hindsight <a href="http://en.wikipedia.org/wiki/Teleonomy">by natural selection</a>. The over-arching goals of survival and reproduction, and the subsidiary goals of feeding, mating, avoiding predators, nurturing young, etc., come pre-wired in the system through millions of years of evolution.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now, there’s a big difference between saying higher-order design principles and evolutionary imperatives <i style="mso-bidi-font-style: normal;">constrain</i> the arrangements of neural systems over long timeframes and claiming that top-down meaning <i style="mso-bidi-font-style: normal;">directs</i> the movements of molecules on a moment-to-moment basis. Most bottom-up reductionists would admit the former but challenge the latter. How can something abstract like meaning push molecules around?</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Determinism, randomness and causal slack</span></b></div><div class="MsoNormal"><a href="http://ie.ign.com/articles/2013/09/12/transporter-prank-used-to-promote-star-trek-into-darkness" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://ie.ign.com/articles/2013/09/12/transporter-prank-used-to-promote-star-trek-into-darkness" border="0" src="http://4.bp.blogspot.com/-kjrNVSJj9oE/VHL_WSU_2eI/AAAAAAAAAqE/vH5XNLjNtOw/s1600/Star%2BTrek.jpg" height="190" width="320" /></a><span lang="EN-GB">The whole premise of neuroscientific materialism is that all of the activities of the mind emerge from the actions and interactions of the physical components of the brain – <i style="mso-bidi-font-style: normal;">and nothing else</i>. If you were transported, Star Trek-style, so that all of your molecules and atoms were precisely recreated somewhere else, the resultant being <i style="mso-bidi-font-style: normal;">would be you</i> – it would have all the knowledge and memories, the personality traits and psychological characteristics you have – in short, precisely duplicating your brain down to the last physical detail, would duplicate your mind. All those immaterial things that make your mind yours must be encoded in the physical <a href="http://www.wiringthebrain.com/2011/07/on-discovering-youre-android.html">arrangement of molecules</a> in your brain right at this moment, as you read this.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">To some (see examples below, in footnote), this implies a kind of neural <a href="http://en.wikipedia.org/wiki/Determinism">determinism</a>. The idea is that, given a certain arrangement of atoms in your brain right at this second, the laws of physics that control how such particles interact (the strong and weak nuclear forces and the gravitational and electromagnetic forces), will lead, <b style="mso-bidi-font-weight: normal;"><i style="mso-bidi-font-style: normal;">inevitably</i></b>, to a specific subsequent state of the brain. In this view, it doesn’t matter what the arrangements of atoms <i style="mso-bidi-font-style: normal;">mean</i>, the individual atoms will behave how they will behave regardless. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">To me, this deterministic model of the brain falls at the first hurdle, for one simple reason – we know that the universe is not deterministic. If it were, then everything that happened since the Big Bang and everything that will happen in the future would have been predestined by the specific arrangements and states of all the molecules in the universe at that moment. Thankfully, the universe doesn’t work that way – there is substantial randomness at all levels, from quantum uncertainty to thermal fluctuations to emergent noise in complex systems, such as living organisms. I don’t mean just that things are so complex or chaotic that they are unpredictable in practice – that is a statement about us, not about the world. I am referring to the <a href="http://www.askamathematician.com/2009/12/q-do-physicists-really-believe-in-true-randomness/">true randomness</a> that <a href="http://en.wikipedia.org/wiki/Bell%27s_theorem">demonstrably exists</a> in the universe, which makes nature essentially non-deterministic. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now, if you are looking for something to rescue free will from determinism, randomness by itself does not do the job – after all, random “choices” are hardly freely willed. But that randomness, that lack of determinacy, does introduce some room, some causal slack, for top-down forces to causally influence the outcome. It means that the next lower-level state of all of the components of your brain (which will entail your next action) is <i style="mso-bidi-font-style: normal;">not</i> completely determined merely by the individual states of all the molecular and atomic components of your brain right at this second. There is therefore room for the higher-order arrangements of the components to also have causal power, precisely because those arrangements represent things (percepts, beliefs, goals) – they have meaning that is not captured in lower-order descriptions. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Information and Meaning </span></b></div><div class="MsoNormal"><span lang="EN-GB">In <a href="http://en.wikipedia.org/wiki/Information_theory">information theory</a>, a message (a string or sequence of digits, letters, beeps, atoms, anything at all really) has a quantifiable amount of information proportional to how unlikely that particular arrangement is. So, there’s more information in knowing that a roll of a six-sided die ended up a four than in knowing that a flip of a coin ended up heads. That’s important for signal transmission especially because it determines how compressible a message is and how efficiently it can be encoded and transmitted, especially under imperfect or noisy conditions. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Interestingly, that measure is analogous to the thermodynamic property of <a href="http://en.wikipedia.org/wiki/Entropy_in_thermodynamics_and_information_theory">entropy</a>, which can be thought of as an inverse measure of how much order there is in a system. This reflects how likely it is to be in the state that it’s in, relative to the total number of such states that it <i style="mso-bidi-font-style: normal;">could have been in</i> (the coin could only have been in two states, while the die could have been in six). In physical terms, the entropy of a gas, for example, corresponds to how many different organisations or microstates of its molecules would correspond to the same macrostate, as characterised by specific temperature and pressure.<span style="mso-spacerun: yes;">&nbsp; </span></span><br /><div class="separator" style="clear: both; text-align: center;"><span lang="EN-GB"><span style="mso-spacerun: yes;"><a href="http://www.science4all.org/le-nguyen-hoang/entropy/"><img alt="http://www.science4all.org/le-nguyen-hoang/entropy/ " border="0" src="http://1.bp.blogspot.com/-PcQat1Xvbm4/VHL_HQNSR5I/AAAAAAAAAp8/8KzPGSLZpik/s1600/entropy.jpg" height="146" width="400" /></a></span></span></div></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Actually, this analogy is not merely metaphorical – it is literally true that information and entropy measure the same thing. That is because information can’t just exist by itself in some ethereal sense – it has to be instantiated in the physical arrangement of some substrate. <a href="http://en.wikipedia.org/wiki/Entropy_in_thermodynamics_and_information_theory#Landauer.27s_principle">Landauer</a> recognised that “</span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">any information that has a physical representation must somehow be embedded in the statistical mechanical degrees of freedom of a physical system”. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">However, “</span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">entropy only takes into account the probability of observing a specific event, so the information it encapsulates is information about the <a href="http://en.wikipedia.org/wiki/Entropy_%28information_theory%29">underlying probability distribution</a>, not the meaning of the events themselves.” In fact, the information theory sense of information is not concerned at all with the <a href="http://plato.stanford.edu/entries/information-semantic/">semantic content</a>of the message. For sentences in a language or for mathematical expressions, for example, information theory doesn’t care if the string is well-formed or whether it is true or not. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">So, the string: “your mother was a hamster” has the same information content as its anagram “warmth or easy-to-use harm”, but only the former has semantic content – i.e., it means something. However, that meaning is not solely inherent in the string itself – it relies on the receiver’s knowledge of the language and their resultant ability to interpret what the individual words mean, what the phrase means and, further, to be aware that it is intended as an insult. The string only means something in the context of that knowledge. </span><br /><div class="separator" style="clear: both; text-align: center;"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"><a href="http://www.quickmeme.com/meme/36eya0"><img alt="http://www.quickmeme.com/meme/36eya0" border="0" src="http://2.bp.blogspot.com/-44SG1ZmY_fU/VHL_u1Ew5HI/AAAAAAAAAqM/p8B8naHwsAs/s1600/your%2Bmother%2Bwas%2Ba%2Bhamster.jpg" height="210" width="400" /></a></span></div></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In the nervous system, information is physically carried in the arrangements of molecules at the cellular level and in the patterns of electrical activity of neurons. For sensory information, this pattern is imposed by physical objects or forces from the environment (e.g., photons, sound waves, odor molecules) impinging on sensory neurons and directly inducing molecular changes and neuronal activity. The resultant patterns of activity thus form a <i style="mso-bidi-font-style: normal;">representation</i>of something in the world and therefore have information – order is enforced on the system, driving one particular pattern of activity from an enormous possible set of microstates. This is true not just for information about sensory stimuli but also for representations of internal states, emotions, goals, actions, etc. All of these are physically encoded in patterns of nerve cell activity. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">These patterns carry information in different ways: in gradients of electrical potential in dendrites (an analog signal), in the firing of action potentials (a digital signal), in the temporal sequence of spikes from individual neurons (a temporally integrated signal), in the spatial patterns of coincident firing across an ensemble (a spatially integrated signal), and even in the trajectory of a network through state-space over some period of time (a spatiotemporally integrated signal!). The operations that carry out the spatial and temporal integration occur in the process of transmitting the information from one set of neurons to another. It is thus the higher-order patterns that encode information rather than the lower-order details of the arrangements of all the molecules in the relevant neurons at any given time-point.</span><br /><br /><span lang="EN-GB">But we’re not done yet. Just like that sentence about your mother (yeah, I went there), for that semantic content to mean anything to the organism it has to be interpreted, and that can only occur in the much broader context of everything the organism knows. (That’s why the French provocateur spoke in English to the stupid English knights, instead of saying “votre mère était un hamster”. Not much point insulting someone if they don’t know what it means).</span><br /><span lang="EN-GB"><br /></span><span lang="EN-GB">The brain has two ways of representing information – one for transmission and one for storage. While information is transmitted in the flow of electrical activity in networks of neurons, as described above, it is stored at a biochemical and cellular level, through changes to the neural network, especially to the synaptic connections between neurons. Unlike a computer, the brain stores memory by changing its own hardware. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Electrical signals are transformed into chemical signals at <a href="http://en.wikipedia.org/wiki/Synapse">synapses</a>, where <a href="http://en.wikipedia.org/wiki/Neurotransmitter">neurotransmitters</a> are released by one neuron and detected by another, in turn inducing a change in the electrical activity of the receiving neuron. But synaptic transmission also induces biochemical changes, which can act as a short-term or a long-term record of activity. Those changes can alter the strength or dynamics of the synapse, so that the next time the presynaptic neuron fires an electrical signal, the output of the postsynaptic neuron will be different. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">When such changes are implemented across a network of neurons, they can make some patterns of activity easier to activate (or reactivate) than others. This is thought to be the cellular basis of memory – not just of overt, conscious memories, but also the implicit, subconscious memories of all the patterns of activity that have happened in the brain. Because these patterns comprise representations of external stimuli and internal states, their history reflects the history of an organism’s experience. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So, each of our brains has been literally physically shaped by the events that have happened to us. That arrangement of weighted synaptic connections constitutes the physical instantiation of our past experience and accumulated knowledge and provides the context in which new information is interpreted. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">But I think there are still a couple elements missing to really give significance to information. The first is <a href="http://en.wikipedia.org/wiki/Salience_%28neuroscience%29">salience</a> – some things are more important for the organism to pay attention to at any given moment than others. The brain has systems to attribute salience to various stimuli, based on things like novelty, relevance to a current goal (food is more salient when you are hungry, for example), current threat sensitivity and recent experience (e.g., a loud noise is less salient if it has been preceded by several quieter ones).</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The second is value – our brains assign positive or negative value to things, in a way that reflects our goals and our evolutionary imperatives. Painful things are bad; things that smell of bacteria are bad; things that taste of bitter/likely poisonous compounds are bad; social defeat is bad; missing Breaking Bad is bad. Food is good; unless you’re dieting in which case not eating is good; an opportunity to mate is (very) good; a pay raise is good; finally finishing a blogpost is good. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The value of these things is not intrinsic to them – it is a response of the organism, which reflects both evolutionary imperatives and current states and goals (i.e., <i style="mso-bidi-font-style: normal;">purpose</i>). This isn’t done by magic – salience and value are <a href="http://www.ncbi.nlm.nih.gov/pubmed/8008189">attributed</a> by <a href="http://en.wikipedia.org/wiki/Neuromodulation">neuromodulatory</a> systems that help set the responsiveness of other circuits to various types of stimuli. They effectively change the weights of synaptic connections and reconfigure neuronal networks, but they do it on the fly, like a sound engineer increasing or decreasing the volume through different channels.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Top-down control and the emergence of agency</span></b></div><div class="MsoNormal"><span lang="EN-GB">The hierarchical, multi-level structure of the brain is the essential characteristic that allows this meaning to emerge and have causal power. Information from lower-level brain areas is successively integrated by higher-level areas, which eventually propose possible actions based on the expected value of the predicted outcomes. The whole point of this design is that higher levels do not care about the minutiae at lower levels. In fact, the connections between sets of neurons are often explicitly designed to act as filters, actively excluding information outside of a specific spatial or temporal frequency. Higher-level neurons extract symbolic, higher-order information inherent in the patterned, dynamic activity of the lower level (typically integrated over space and time) in a way that does not depend on the state of every atom or the position of every molecule or even the activity of every neuron at any given moment. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There may be <a href="http://www.thedivineconspiracy.org/Z5235Y.pdf">infinite arrangements</a> of all those components at the lower level that mean the same thing (that represent the same higher-order information) and that would give rise to the same response in the higher-level group of neurons. Another way to think about this is to assess causality in a counterfactual sense: instead of asking whether state A necessarily leads to state B, we can ask: if state A had been different, would state B still have arisen? If there are cases where that is true, then the full explanation of why state A leads to state B does not inhere solely in its lower-level properties. Note that this does not violate physical laws or conflict with them at all – it simply adds another level of causation that is required to explain <i style="mso-bidi-font-style: normal;">why</i> state A led to state B. The answer to that question lies in what state A means to the organism.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">To reiterate, the meaning of any pattern of neural activity is given not just by the information it carries but by the implications of that information for the organism. Those implications arise from the experiences of the individual, from the associations it has made, the contingencies it has learned from and the values it has assigned to past or predicted outcomes. This is what the brain is for – learning from past experience and abstracting the most general possible principles in order to assign value to predicted outcomes of various possible actions across the widest possible range of new situations. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="https://www.flickr.com/photos/nossreh/10987353554/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="https://www.flickr.com/photos/nossreh/10987353554/" border="0" src="http://1.bp.blogspot.com/-6LPoowFgAYo/VHMAFkXs4LI/AAAAAAAAAqU/o105ToyCOcg/s1600/agent%2Bsmith.jpg" height="150" width="200" /></a><span lang="EN-GB">This is how true <i style="mso-bidi-font-style: normal;">agency</i> can emerge. The organism escapes from a passive, deterministic stimulus-response mode and ceases to be an automaton. Instead, it becomes an active and <a href="http://plato.stanford.edu/entries/personal-autonomy/">autonomous entity</a>. It chooses actions based on the meaning of the available information, <i style="mso-bidi-font-style: normal;">for that organism</i>, weighted by values based on <i style="mso-bidi-font-style: normal;">its own</i> experiences and <i style="mso-bidi-font-style: normal;">its own</i> goals and motives. In short, it ceases to be pushed around, offering no resistance to every causal force, and becomes a cause in its own right.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This kind of <a href="http://en.wikipedia.org/wiki/Emergence">emergence</a> doesn’t violate physical law. The system is still built of atoms and molecules and cells and circuits. And changes to those components will still affect how the system works. But that’s not all the system is. Complex, hierarchical and recursive systems that incorporate information and meaning and purpose produce astonishing and still-mysterious (but non-magical) emergent properties, like life, like consciousness, like will. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Just because it’s <a href="http://en.wikipedia.org/wiki/Turtles_all_the_way_down">turtles all the way down</a>, doesn’t mean it’s turtles all the way up.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /><br /><br /><br /><b>Footnote: </b>Here are some examples of prominent scientists and others who support the idea of a deterministic universe and who infer that free will is therefore an illusion (except Dennett and other compatibilists): <br /><br />Stephen Hawking: "…the molecular basis of biology shows that biological processes are governed by the laws of physics and chemistry and therefore are as determined as the orbits of the planets. Recent experiments in neuroscience support the view that it is our physical brain, following the known laws of science, that determines our actions and not some agency that exists outside those laws…so it seems that we are no more than biological machines and that free will is just an illusion (Hawking and Mlodinow, 2010, emphasis added)." Quoted in this excellent blogpost: <a href="http://www.sociology.org/when-youre-wrong-youre-right-stephen-hawkings-implausible-defense-of-determinism/">http://www.sociology.org/when-youre-wrong-youre-right-stephen-hawkings-implausible-defense-of-determinism/</a><br /><br />Patrick Haggard: "As a neuroscientist, you've got to be a determinist. There are physical laws, which the electrical and chemical events in the brain obey. Under identical circumstances, you couldn't have done otherwise; there's no 'I' which can say 'I want to do otherwise'. It's richness of the action that you do make, acting smart rather than acting dumb, which is free will." <br /><a href="http://www.telegraph.co.uk/science/8058541/Neuroscience-free-will-and-determinism-Im-just-a-machine.html">http://www.telegraph.co.uk/science/8058541/Neuroscience-free-will-and-determinism-Im-just-a-machine.html</a><br /><br />Sam Harris: "How can we be “free” as conscious agents if everything that we consciously intend is caused by events in our brain that we do not intend and of which we are entirely unaware?" <a href="http://www.samharris.org/free-will">http://www.samharris.org/free-will</a><br /><br />Jerry Coyne: "Your decisions result from molecular-based electrical impulses and chemical substances transmitted from one brain cell to another. These molecules must obey the laws of physics, so the outputs of our brain—our "choices"—are dictated by those laws." <a href="http://chronicle.com/article/Jerry-A-Coyne/131165/">http://chronicle.com/article/Jerry-A-Coyne/131165/</a><br /><br />Daniel Dennett: Who concedes physical determinism is true but sees free will as compatible with that. This is a move that I have never fully understood the logic of or found at all convincing, yet apparently some form of compatibilism is a majority view among philosophers these days. <a href="http://plato.stanford.edu/entries/compatibilism/">http://plato.stanford.edu/entries/compatibilism/</a><br /><br /><br /><br /><br /></div><div class="MsoNormal"><br /><b>Further reading:</b><br /><br />Baumeister RF, Masicampo EJ, Vohs KD. (2011) Do conscious thoughts cause behavior? Annu Rev Psychol. 2011;62:331-61. <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=21126180">http://www.ncbi.nlm.nih.gov/pubmed/?term=21126180</a><br /><br />Björn Brembs (2011) Towards a scientific concept of free will as a biological trait: spontaneous actions and decision-making in invertebrates. Proc Biol Sci. 2011 Mar 22;278(1707):930-9. <a href="http://rspb.royalsocietypublishing.org/content/278/1707/930.full">http://rspb.royalsocietypublishing.org/content/278/1707/930.full</a><br /><br />Bob Doyle (2010) Jamesian Free Will, the Two-Stage Model of William James. William James Studies 2010, Vol. 5, pp. 1-28. <a href="http://williamjamesstudies.org/5.1/doyle.pdf">williamjamesstudies.org/5.1/doyle.pdf</a><br /><br />Buschman TJ, Miller EK.(2014) Goal-direction and top-down control. Philos Trans R Soc Lond B Biol Sci. 2014 Nov 5;369(1655). <a href="http://www.ncbi.nlm.nih.gov/pubmed/25267814">http://www.ncbi.nlm.nih.gov/pubmed/25267814</a><br /><br />Damasio, Antonio (1994). Descartes' Error: Emotion, Reason, and the Human Brain, HarperCollins Publisher, New York.<br /><br />George Ellis (2009) Top-Down Causation and the Human Brain. In Downward Causation and the Neurobiology of Free Will. Nancey Murphy, George F.R. Ellis, and Timothy O’Connor (Eds.) Springer-Verlag Berlin Heidelberg <a href="http://www.thedivineconspiracy.org/Z5235Y.pdf">www.thedivineconspiracy.org/Z5235Y.pdf</a><br /><br />Friston K. (2010) The free-energy principle: a unified brain theory? Nat Rev Neurosci. 2010 Feb;11(2):127-38. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20068583">http://www.ncbi.nlm.nih.gov/pubmed/20068583</a><br /><br />James Gleick (2011) The Information: A History, a Theory, a Flood <a href="http://www.amazon.com/The-Information-History-Theory-Flood/dp/1400096235">http://www.amazon.com/The-Information-History-Theory-Flood/dp/1400096235</a><br /><br />Paul Glimcher: Indeterminacy in brain and behavior. Annu Rev Psychol. 2005;56:25-56. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15709928">http://www.ncbi.nlm.nih.gov/pubmed/15709928</a><br /><br />Douglas Hofstadter (1979) Gödel, Escher, Bach <a href="http://www.physixfan.com/wp-content/files/GEBen.pdf">www.physixfan.com/wp-content/files/GEBen.pdf</a><br /><br />Douglas Hofstadter (2007) I am a Strange Loop <a href="http://occupytampa.org/files/tristan/i.am.a.strange.loop.pdf">occupytampa.org/files/tristan/i.am.a.strange.loop.pdf</a><br /><br />William James (1884) The Dilemma of Determinism. <a href="http://www.rci.rutgers.edu/~stich/104_Master_File/104_Readings/James/James_DILEMMA_OF_DETERMINISM.pdf">http://www.rci.rutgers.edu/~stich/104_Master_File/104_Readings/James/James_DILEMMA_OF_DETERMINISM.pdf</a><br /><br />Roger Sperry (1965) Mind, brain and humanist values. In New Views of the Nature of Man. ed. J. R. Platt, University of Chicago Press, Chicago, 1965. <a href="http://www.informationphilosopher.com/solutions/scientists/sperry/Mind_Brain_and_Humanist_Values.html">http://www.informationphilosopher.com/solutions/scientists/sperry/Mind_Brain_and_Humanist_Values.html</a><br /><br />Roger Sperry (1991) In defense of mentalism and emergent interaction. Journal of Mind and Behavior 12:221-245 (1991) &nbsp;<a href="http://people.uncw.edu/puente/sperry/sperrypapers/80s-90s/270-1991.pdf">http://people.uncw.edu/puente/sperry/sperrypapers/80s-90s/270-1991.pdf</a></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2014/11/top-down-causation-and-emergence-of.htmlnoreply@blogger.com (Kevin Mitchell)32tag:blogger.com,1999:blog-6146376483374589779.post-5834058202645418039Mon, 03 Nov 2014 11:16:00 +00002014-11-03T03:16:34.449-08:00autismcausationenvironmentepidemiologygeneticsAutism, epidemiology, and the public perception of evidence<div dir="ltr" style="text-align: left;" trbidi="on">“One day it's C-sections, the next it's pollution, now so many genes. Connect the dots, causation changes like the wind” <br /><br />That quote is from a brief conversation I had on Twitter recently, with someone who is sceptical of the evidence that the causes of autism are overwhelmingly genetic (as described <a href="http://www.wiringthebrain.com/2014/10/autism-truth-is-not-out-there.html">here</a>). For me, it sums up a huge problem in how science is reported and perceived by the general public. This problem is especially stark when it comes to reportage of <a href="http://en.wikipedia.org/wiki/Epidemiology">epidemiology</a> studies, which seem to attract disproportionate levels of press interest. <br /><br />The problem was highlighted by reports of a recent study that claims to show a statistical link between delivery by <a href="http://en.wikipedia.org/wiki/Caesarean_section">Caesarean section</a> and risk of autism. This study was reported in several Irish newspapers, with alarming headlines like “<a href="http://www.independent.ie/breaking-news/irish-news/csections-raise-autism-risk-30695142.html">C-sections ‘raise autism risk</a>’” and in the UK Daily Mail, whose headline read (confusingly): “<a href="http://www.dailymail.co.uk/health/article-2808901/Autism-23-likely-babies-born-C-section-Women-warned-not-alarmed-findings-risk-remains-small.html">Autism '23% more likely in babies born by C-section': Women warned not to be alarmed by findings because risk still remains small</a>”. <br /><br />The <a href="http://onlinelibrary.wiley.com/doi/10.1111/jcpp.12351/abstract">study in question</a> was a <a href="http://en.wikipedia.org/wiki/Meta-analysis">meta-analysis</a> – a statistical analysis of the results of many previous studies – which looked at rates of autism in children delivered by C-section versus those delivered by vaginal birth. Across 25 studies, the authors found evidence of a 23% increased risk of autism in children delivered by C-section – a finding reported by all of the newspaper articles and cited in several of the headlines. <br /><br />23% increased risk!!! That sounds huge! It almost sounds like 1 in 4 kids delivered by C-section will get autism. It also sounds like it is the fact that they were delivered by C-section that would be the cause of them having autism. In fairness, that’s not what the study or the newspaper articles say – in fact, there are any number of caveats and qualifications in these reports that should mitigate against such conclusions being drawn. But they won’t.<br /><br /><div class="separator" style="clear: both; text-align: center;"><a href="http://nourishbaby.com.au/blogs/news/8173077-preparing-for-an-elective-c-section-birth" style="margin-left: 1em; margin-right: 1em;"><img alt="http://nourishbaby.com.au/blogs/news/8173077-preparing-for-an-elective-c-section-birth" border="0" src="http://4.bp.blogspot.com/-ViL-OwtC7U8/VFdjcIjPz5I/AAAAAAAAApY/Bdt7PmMrpGE/s1600/C-section.jpg" height="225" width="400" /></a></div><br />They won’t because most people will only see or will only remember the headlines. It is the juxtaposition of the two terms – C-sections, autism – that will stick in people’s minds. <br /><br />Most people not trained in epidemiology are not well equipped to evaluate the strength of the evidence, the size of the effect or the interpretation of causality from statistical associations. That should be the job of a science reporter, but it was not done in this case. In fact, most of the articles read like (and presumably are) merely a slightly re-hashed press release, the job of which is obviously to make the results sound as significant as possible. They include no critical commentary, no perspective or explanation and no judgment about whether the findings of this study are newsworthy to begin with. <br /><br />For any study of this kind, you can ask several questions: 1. Is the evidence for an effect solid? 2. Is the effect significant (as in substantial)? 3. What does the effect mean? And a responsible journalist (or scientist thinking of whether or not to issue a press release) might also ask themselves: 4. Could uncritical reporting of these findings be misinterpreted and cause harm?<br /><br />So, let’s have a look at the details here and see if we can answer those questions. In this study, published in the Journal of Child Psychology and Psychiatry, the authors look at the results of 25 previously published studies that investigated a possible link between C-sections and autism. These studies vary widely in size and methodologies (was it an elective or emergency C-section, a case-control or cohort study, were siblings used as controls, were the findings adjusted for confounders such as maternal age or smoking during pregnancy or gestational age at delivery, was autism the only outcome or were other things measured, was C-section the only risk factor or were other factors included, etc., etc.).<br /><br />The point of a meta-analysis is for the authors to devise ways to statistically correct for these different approaches and combine the data to derive an overall conclusion that is supposed to be more reliable than findings from any one study. The authors make a series of choices of which studies to include, what weight to give them and how to statistically combine them. These choices are all reported, of course, but the point is that different choices and approaches might lead to different answers. <br /><br /><br />In this case, the authors concentrate on 13 studies that adjusted for potential confounds (as much as any epidemiological study can). Each of these compares the frequency of autism in a cohort of children delivered by C-section with that in a group of children delivered vaginally. A difference in frequency is described by the <a href="http://en.wikipedia.org/wiki/Odds_ratio">odds ratio</a> (OR) – if the rates are equal, then the OR=1. If the rate is, say 10% higher in those delivered by C-section, then the OR=1.1. The results of these studies are shown below:<br /><br /><br /><div class="separator" style="clear: both; text-align: center;"></div><div class="separator" style="clear: both; text-align: center;"><a href="http://4.bp.blogspot.com/-dHuOmgl8RtE/VFddLNJKEAI/AAAAAAAAApI/hYKGGN1Sank/s1600/Screen%2BShot%2B2014-11-03%2Bat%2B8.02.09%2BAM.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-dHuOmgl8RtE/VFddLNJKEAI/AAAAAAAAApI/hYKGGN1Sank/s1600/Screen%2BShot%2B2014-11-03%2Bat%2B8.02.09%2BAM.png" height="264" width="640" /></a></div><br />One important thing jumps out – some of these studies have vastly more subjects than others. (For some reason, the numbers in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050963">Langridge et al 2013</a> study are not listed in the table: it had 383,000 children in total). What should be obvious is that the studies showing the biggest odds ratios (5.60 or 3.11) are the ones with the smallest sample sizes (n = 278 or 146). The biggest studies (with n &gt; 690,000 or &gt;268,000!) show either negative or very small positive odds ratios (0.97 or 1.04). <br /><br />Now, why you would want to combine results from studies with samples in the hundreds, with those with samples in the hundreds of thousands is beyond me and the way the authors do it also seems odd. In order to combine them, the odds ratios of these studies are weighted by the inverse of the <a href="http://en.wikipedia.org/wiki/Variance">variance</a> in each study. Maybe that’s a standard meta-analysis thing to do, but it seems much more intuitive to weight them by the sample size (or just get rid of the ones with dinky sample sizes). When you do it that way, the overall odds ratio comes out barely over 1. (This doesn’t even take into account possible publication bias, where studies that found no effect were never even published).<br /><br />Anyway, all of that discussion is merely to draw attention to the fact that the methodological choices of the authors can influence the outcome. The headline reported 23% increase in risk is thus not necessarily a solid finding. <br /><br />But, for the sake of argument, let’s take it at face value and try to express what it actually means in ways that people can understand. The problem with odds ratios is they represent an increase in risk, compared to the baseline risk, which is very small. So, the 23% increased risk really is not an increase in absolute risk, as it sounds, but a relative increase by 23% of the baseline risk, which is about 1% (so really an increase of 0.23%). <br /><br />A clearer way to report that is to express it in <a href="http://www.badscience.net/2005/06/risky-business/">natural frequencies</a>: if the base rate of autism is ~10 children out of 1,000, you would expect ~12 with autism out of 1,000 children all delivered by C-section. Those are numbers that people can grasp intuitively (and most people would see that the supposed increase is fairly negligible – that is, there’s not much of a difference between 10/1,000 and 12/1,000). Certainly nothing newsworthy.<br /><br />But let’s say it’s a slow news day and we have this pre-prepared press release describing these findings in front of us and space to fill. What should we say about what this statistical association means? Does such a correlation imply that one thing causes the other thing? Is it evidence that the fact of being delivered by C-section is the cause of an increased risk of autism? <br /><br />I think most people can see that it does not, at least not necessarily. It is of course possible that the link is causal and direct. But it seems much more likely that the C-section is merely an indicator of obstetric complications, which are themselves a statistical risk factor for autism. (In which case, having the section is likely to reduce, not increase the chances of harm!). Moreover, obstetric complications can arise due to an underlying condition of the fetus. In such a case, the arrow of causation would be exactly opposite to what it appears – the child having a neurodevelopmental condition would be the cause of the C-section. <br /><br />So, to answer questions 1-3: the findings are not necessarily as solid as they appear, the size of the effect is nowhere near as large as the “23% increased” risk phrase suggests, and, even if the actually small effect were real, it does not imply that C-sections are a bad thing. <br /><br />Now, for question 4: if this finding is reported, is it likely to be misunderstood (despite a wealth of caveats) and is that misunderstanding likely to cause harm? In this case, for an emotive and already confused issue like autism, the answer to both those questions is pretty obviously yes. It doesn’t take much imagination to see the effect on pregnant women faced with the decision of whether to undergo a C-section, possibly in difficult and stressful circumstances. It seems a very real possibility that this perceived risk could lead some women to refuse or delay a C-section, which could actually increase the rates of neurodevelopmental disorders due to obstetric complications.<br /><br />More generally, the reportage of this particular study illustrates a much wider problem, which is that the media seem fascinated with epidemiology studies. One reason for this is that such studies typically require no background knowledge to understand. You don’t need to know any molecular or cell biology, any complicated genetics or neuroscience, to (mis)understand the idea that X is associated with increased risk of Y. That makes it easy for reporters to write and superficially accessible for a wide readership. <br /><br />Unfortunately, it leads to two effects: one, people will misinterpret the findings and ascribe a high level of risk and a direct causal influence to some factor when the evidence does not support that at all. That has potential to do real harm, as in the case of reduced vaccination, for example. <br /><br />The second effect is more insidious – people get jaded by these constant reports in the media. First, butter was bad for us, now it’s good for us, first fat was bad for us, now it’s sugar, etc., etc. The overall result of this constant barrage of rubbish findings is that the general public loses faith in science. If we apparently change our minds on a weekly basis, why should they trust anything we say? All science ends up being viewed as equivalent to epidemiology, which is really not what <a href="http://en.wikipedia.org/wiki/Thomas_Kuhn">Thomas Kuhn</a> has called “<a href="http://en.wikipedia.org/wiki/Normal_science">normal science</a>”. <br /><br />Normal science involves an established framework of inter-supporting facts, which constrain and inform subsequent hypotheses and experiments, so that any new fact is based on and consistent with an unseen mountain of previous work. That is not the case for epidemiology – you could do a study on C-sections and autism pretty much on a whim – that hypothesis is not constrained by a large framework of research (except previous research on precisely that issue). I don’t mean to knock epidemiology as an exploratory science, just to illustrate its well-known limitations. <br /><br />In the case of autism, this leads people like our tweeter, above, to erroneously take the strength of the evidence for C-sections or pollution or genetics as equivalent (and, in this case, to dismiss all of it as just the flavour of the month). That seriously undermines efforts to communicate what is an <a href="http://www.wiringthebrain.com/2014/10/autism-truth-is-not-out-there.html">exceptionally robust framework of evidence</a> for genetic causation of this condition. The answer is not blowing in the wind...<br /><br /></div>http://www.wiringthebrain.com/2014/11/autism-epidemiology-and-public.htmlnoreply@blogger.com (Kevin Mitchell)3tag:blogger.com,1999:blog-6146376483374589779.post-389016659276822800Sun, 19 Oct 2014 16:15:00 +00002014-10-19T09:15:50.968-07:00autismclinical geneticsgeneticgenetic architecturegeneticsmutationsrare disordersrare mutationswhole-genome sequencingAutism: The Truth is (not) Out There <div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoHeader, li.MsoHeader, div.MsoHeader {mso-style-priority:99; mso-style-link:"Header Char"; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; tab-stops:center 3.0in right 6.0in; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoFooter, li.MsoFooter, div.MsoFooter {mso-style-priority:99; mso-style-link:"Footer Char"; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; tab-stops:center 3.0in right 6.0in; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; mso-themecolor:hyperlink; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} span.st {mso-style-name:st; mso-style-unhide:no;} span.HeaderChar {mso-style-name:"Header Char"; mso-style-priority:99; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:Header;} span.FooterChar {mso-style-name:"Footer Char"; mso-style-priority:99; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:Footer;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style><span lang="EN-GB">Parents of a child affected by autism naturally want to know the cause. Autism can dramatically disrupt the typical childhood pattern of cognitive, behavioural and social development. At the most severe end, the child may require care for the rest of their lives. Even at the milder end, it may make mainstream education impossible and exclude many opportunities available to typically developing children. Any parent would hope that knowing the cause could lead to better treatment and management options for their child. </span> <br /><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Unfortunately, until very recently, it has not been possible to identify causes in individual children (with rare exceptions). Science and medicine had apparently failed to solve this mystery. (I say “had”, because, as we will see below, this is no longer true). The typical experience of children and their parents in the health system has been one of frustration, often with a long diagnostic odyssey, limited options for medical intervention and a struggle to obtain access to specialised educational services – all during a critical period in the child’s development. Given this frustration, it is understandable that a variety of alternative theories of autism causation have become popular. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://news.bme.com/tag/geek/page/9/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://news.bme.com/tag/geek/page/9/" border="0" src="http://1.bp.blogspot.com/-HYvRFRWvV7c/VEPY4XwwYVI/AAAAAAAAAnc/mKwGHc4X1H8/s1600/truth%2Bis%2Bout%2Bthere.jpg" height="182" width="320" /></a><span lang="EN-GB">Parents should beware, however – while such theories appeal to those common frustrations, they generally have no scientific support whatsoever. Many of these are not just <i style="mso-bidi-font-style: normal;">non</i>-scientific, but actively <i style="mso-bidi-font-style: normal;">anti</i>-scientific in nature. They tend to be based on anecdote, narrative and outright speculation, rather than the scientific method (objective assessment of empirical evidence). Many play to conspiracy theories, casting scientists and doctors as pawns of Big Pharma, for example, and those proposing alternative theories as brave mavericks fighting against the establishment to get The Truth out there. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Ironically, the truth is that many of the people pushing alternative theories are looking to make money off them – often by taking advantage of vulnerable parents. Not all, by any means, but very often a commercial interest is not hard to find (such as selling costly diets or supplements or even more dangerous supposed “<a href="http://www.forbes.com/sites/emilywillingham/2013/10/29/the-5-scariest-autism-treatments/">treatments</a>”; claims that alternative therapies like homeopathy can cure the condition; pricey seminars; or a new book to promote)*. Alternative theories for autism and the treatments that go with them are big business. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The other irony is that these theories actively ignore our growing knowledge of the real causes of autism, which are clearly mainly genetic. The Truth is known but it’s <i style="mso-bidi-font-style: normal;">not</i>out there. Scientists have done a poor job of communicating the extraordinary advances made in the last few years in understanding the genetic causes of autism. (Even many scientists and doctors seem unaware of these advances, in fact). This leaves a void that can be filled by theories that are highly speculative or sometimes frankly bizarre, and that are also either unsupported or flatly contradicted by available evidence.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">The unusual suspects</span></b></div><div class="MsoNormal"><a href="http://www.mnn.com/green-tech/gadgets-electronics/blogs/best-ipad-apps-for-toddlers" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://www.mnn.com/green-tech/gadgets-electronics/blogs/best-ipad-apps-for-toddlers" border="0" src="http://1.bp.blogspot.com/-ZSOiSe13oV8/VEPZqlKS53I/AAAAAAAAAnk/tDktmJEzHmc/s1600/iPad%2Btoddler.jpg" height="181" width="320" /></a><span lang="EN-GB">The old psychoanalytical theory that autism is caused by “cold parenting” has long since been discredited, but still pops up every now and then (and is still quite prevalent in <a href="http://deevybee.blogspot.ie/2012/01/psychoanalytic-treatment-for-autism.html">France</a> and Argentina, for some reason). It is often <a href="http://www.broadsheet.ie/2012/02/08/that-tony-humphreys-autism-article-in-full/">espoused</a> by people who also happen to offer psychological courses that purport to realign this relationship and thereby ameliorate the condition. Bizarrely, this theory has been resurrected in modern form by neuroscientist Susan Greenfield, who <a href="http://www.theguardian.com/science/the-lay-scientist/2011/aug/08/1">has suggested</a> that autism is caused by overuse of digital technology and immersion in social media, with a concomitant withdrawal from direct human contact. The refrigerator mother has been replaced by the unfeeling screen of the iPad. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This technophobic notion is largely <a href="http://deevybee.blogspot.ie/2014/09/why-most-scientists-dont-take-susan.html">incoherent</a>and has no supporting evidence. (When asked for evidence, Greenfield has described her own theory as follows: </span><span class="st"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">"I </span></span><em><span lang="EN-GB" style="font-family: Cambria; font-style: normal; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-bidi-font-style: italic; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-theme-font: minor-latin;">point</span></em><span class="st"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">to the<i style="mso-bidi-font-style: normal;"> </i></span></span><em><span lang="EN-GB" style="font-family: Cambria; font-style: normal; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-bidi-font-style: italic; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-theme-font: minor-latin;">increase in autism</span></em><span class="st"><i style="mso-bidi-font-style: normal;"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"> </span></i></span><span class="st"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">and I<i style="mso-bidi-font-style: normal;"> </i></span></span><em><span lang="EN-GB" style="font-family: Cambria; font-style: normal; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-bidi-font-style: italic; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-theme-font: minor-latin;">point</span></em><span class="st"><i style="mso-bidi-font-style: normal;"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"> </span></i></span><span class="st"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">to<i style="mso-bidi-font-style: normal;"> </i></span></span><em><span lang="EN-GB" style="font-family: Cambria; font-style: normal; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-bidi-font-style: italic; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-theme-font: minor-latin;">internet use</span></em><span class="st"><i style="mso-bidi-font-style: normal;"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">. </span></i></span><span class="st"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">That is<i style="mso-bidi-font-style: normal;"> </i></span></span><em><span lang="EN-GB" style="font-family: Cambria; font-style: normal; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-bidi-font-style: italic; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-theme-font: minor-latin;">all</span></em><span class="st"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">.”)</span></span><span lang="EN-GB">. The fact that autism is typically diagnosed by two or three years of age, well before most kids have Facebook or Twitter accounts, rather fatally undermines the idea. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.misija.com/gmo/vy/15/genetically-modified-food" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.misija.com/gmo/vy/15/genetically-modified-food" border="0" src="http://4.bp.blogspot.com/--igoOfsBhn0/VEPah1rZ72I/AAAAAAAAAns/jgYbMeAB-mI/s1600/toxic%2BGMO.jpg" /></a><span lang="EN-GB">Another class of theories propose that autism is caused not by an impoverished psychosocial environment, but by a toxic physical environment. There is no shortage of potential culprits: fluoride in the water, mercury in dental amalgam, vaccinations, genetically modified food, herbicides, pesticides, food allergies, microwaves, cell phone towers, traffic fumes, even toxins in everyday items like mattresses and dental floss. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">(These days, many of these are given a pseudoscientific gloss by invoking the magic of “<a href="http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-1.html">epigenetics</a>”, a term now so corrupted as to be worse than useless). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">A driving factor behind all of these theories is the fact that rates of autism diagnoses have been increasing steadily in some countries for the past couple decades. This has led some to declare “an autism epidemic”, with the obvious connotation that <i style="mso-bidi-font-style: normal;">something in the environment must be causing it. </i></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This premise is flawed, however, as it assumes the rate of diagnosis mirrors a real rise in the rate of the disease. In fact, the rise in diagnosis rates can be largely explained by better recognition of the condition among doctors and <a href="http://deevybee.blogspot.ie/2011/05/autism-diagnosis-in-cultural-context.html">broader awareness</a> among the general public, and by diagnostic substitution, whereby children who previously would have been given a general diagnosis of mental retardation are now more commonly diagnosed with ASD. After all, <a href="http://en.wikipedia.org/wiki/Leo_Kanner">prior to 1943</a>, <b style="mso-bidi-font-weight: normal;"><i style="mso-bidi-font-style: normal;">no one was diagnosed with autism</i></b>because the term had not yet been applied to this childhood condition. The gradual rise in autism diagnoses following that period could hardly be thought of as signaling a sudden epidemic. The criteria used by psychiatrists to define the condition have changed multiple times over the years, including in the most recent version of the <a href="http://en.wikipedia.org/wiki/DSM-5">DSM</a>, and each change leads to a <a href="http://www.cdc.gov/ncbddd/autism/features/impact-dsm5.html">change in the number of children who fit</a> under this diagnosis. The label is thus artificial and changeable and its application has also varied widely over time. There is no reason to think these variations reflect changes in the rate of the condition itself.</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://depletedcranium.com/what-is-causing-the-autism-epidemic-maybe-noithing/" style="margin-left: 1em; margin-right: 1em;"><img alt="http://depletedcranium.com/what-is-causing-the-autism-epidemic-maybe-noithing/" border="0" src="http://4.bp.blogspot.com/-37ynkg585B4/VEPbq0rjdFI/AAAAAAAAAn4/uHpz2FkqU3U/s1600/autism%2Bvs%2BMR.jpg" height="271" width="400" />&nbsp;</a></div><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="MsoNormal"><span lang="EN-GB">There is, moreover, no evidence linking any of the potential environmental factors listed above to autism. In fact, in many cases, there is very strong evidence <i style="mso-bidi-font-style: normal;">disproving</i>any such link. (See <a href="http://www.forbes.com/sites/emilywillingham/2014/05/15/vaccines-thimerosal-mmr-mercury-not-associated-with-autism/">here</a> and <a href="http://www.cmaj.ca/content/182/4/E199.short">here</a> for a discussion of the absence of any link with vaccination, for example). Regrettably, however, some of these stories simply refuse to die. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Undead memes</span></b></div><div class="MsoNormal"><span lang="EN-GB">Part of their persistence may arise from the way they are framed as anti-mainstream theories – for many adherents this inoculates them against scientific critiques or counter-evidence, due to mistrust of the scientific establishment or a lack of acceptance of the scientific method as a means of objectively discovering the truth. It is, moreover, very difficult to counter emotive personal anecdotes and highly publicised but methodologically flawed studies (some of which have later been retracted or even shown to be fraudulent), with, for example, dry statistical data showing no epidemiological link to vaccines or fluoride or dental floss or any other supposed environmental toxins.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://shortstoriesshort.com/story/noahs-ark/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://shortstoriesshort.com/story/noahs-ark/" border="0" src="http://1.bp.blogspot.com/-ONOiBAIgEAM/VEPdL2wy6dI/AAAAAAAAAoE/39wSdd1NY8A/s1600/Noah's%2Bark.jpg" height="174" width="320" /></a><span lang="EN-GB">In one sense, such arguments grant too much credibility to these theories by allowing the battle to be fought solely on their turf. It puts the onus on scientists to <i style="mso-bidi-font-style: normal;">disprove</i> each new theory. (This is like arguing with creationists by trying to disprove the existence of Noah’s ark, instead of simply presenting the positive evidence for evolution by natural selection). The problem with this is that negative findings are simply not very compelling, psychologically, regardless of the statistical strength of the conclusion. It’s too easy to misinterpret what is really strong evidence that something is <i style="mso-bidi-font-style: normal;">not the case</i> as merely the absence of evidence that it is (which would leave it an open question, requiring “more research”). This means the “is not” side is at a disadvantage in an “is too”/“is not” argument.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In my opinion, the strongest counter-argument is one that is often not mentioned in such discussions – the positive evidence for genetic causation. Instead of expending so much effort trying to prove “it’s not that”, we can simply say “it’s this – look”. There is really no explanatory void to fill. We know what causes autism, in general, and we are identifying more and more of the specific factors that cause it in individuals. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB">Autism is genetic</span></b></div><div class="MsoNormal"><span lang="EN-GB">The evidence that autism is largely genetic is overwhelming – in fact, it is among the most heritable of common disorders. This has been established through family and twin studies that look at the rate of occurrence of the disorder (or statistical “risk”) in relatives of patients with autism. If one child in a family has autism, the risk to subsequent children has been estimated to be between ~10-20%, far higher than the 1% population average. If two children are affected, the risk to another child can be as high as 50%. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now, you might argue that this does not prove genetic influences, as environmental factors may also be shared between family members. Twin studies have been designed for precisely that reason. Here, we compare the risk to one co-twin when the other has a diagnosis of autism, in two cases: when the twins are identical (or monozygotic, sharing 100% of their DNA) versus when they are fraternal (or dizygotic, sharing 50% of their DNA). This design is so powerful because it separates genetic effects from possible environmental ones. Genetic effects should make identical twins more similar than fraternal twins, while environmental effects should not differ between these pairs. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://ngm.nationalgeographic.com/2012/01/twins/schoeller-photography" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://ngm.nationalgeographic.com/2012/01/twins/schoeller-photography" border="0" src="http://1.bp.blogspot.com/-4hUVuqC9paw/VEPdWTpuR7I/AAAAAAAAAoM/hxrsgW3I_oQ/s1600/twins-autism.jpg" height="271" width="320" /></a><span lang="EN-GB">The results are dramatic – </span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">if one of a pair of identical twins is autistic, the chance that the other one will be too is over 80%, while the rate in fraternal twins is less than 20%. (Even in cases when the co-twin does not have a diagnosis of autism, they very often have some other psychiatric diagnosis, again much more so in identical than fraternal co-twins). These results, which have been replicated many times, show that variation across the population in risk of autism is overwhelmingly due to genetic differences. Crucially, these results are not consistent with an important role for variable environmental factors in the etiology of the disorder – these should affect identical and fraternal twins equally. Similarly, full siblings of someone with autism are at ~2 times greater risk than half-siblings, again consistent with genetic but not with environmental causation.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">These kinds of analyses answer the question: in a given population at a given time, <b style="mso-bidi-font-weight: normal;"><i style="mso-bidi-font-style: normal;">why do some people get autism while others don’t</i></b>? The answer is unequivocal – this is overwhelmingly down to genetic differences. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">Finding mutations in specific genes</span></b></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">The fact that autism is largely a genetic disorder has been known for decades. What has not been known is the identity of the specific genes involved, with the exception of a couple examples, involving genes associated with syndromes in which autistic symptoms are common, such as <a href="http://en.wikipedia.org/wiki/Fragile_X_syndrome">Fragile X syndrome</a> or <a href="http://en.wikipedia.org/wiki/Rett_syndrome">Rett syndrome</a>. These syndromes are caused by mutations in specific single genes and account for 3-4% of all autism cases. However, the vast majority of cases were left unexplained, and not for want of looking. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://sparkonit.com/2014/04/30/gene-mutation-that-leads-to-abnormal-development-responsible-for-autism-discovered/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://sparkonit.com/2014/04/30/gene-mutation-that-leads-to-abnormal-development-responsible-for-autism-discovered/" border="0" src="http://2.bp.blogspot.com/-XLABqB-MS94/VEPjd4Ha1uI/AAAAAAAAAo0/xA3svKiW1CU/s1600/mutation-autism.jpg" height="266" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">This apparent failure to find the specific genes involved clearly has led to the impression that genetics can not explain the condition and that other factors must therefore be involved. This is not the case at all – even if we remained completely ignorant of specific causes, the fact that autism is extremely highly heritable would remain just as true. As it happens, the failure to find specific causes had a technical reason – it was simply very difficult to discover the kinds of mutations that cause the condition. This is because such mutations are <a href="http://www.ncbi.nlm.nih.gov/pubmed/20832285">individually very rare</a> in the population and because there is not just one gene involved, or two, or even ten, but probably many hundreds.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">These mutations are now detectable thanks to new technologies that allow the entire genome to be surveyed (either for changes to single letters or bases of DNA or for deletions or duplications of bits of chromosomes). Using these technologies, it has been possible to find over a hundred different genes (or regions of chromosomes) in which a mutation can lead to autism. Collectively, the known causes now account for 20-25% of cases of autism. </span></div><div class="separator" style="clear: both; text-align: center;"><a href="http://ultimateautismguide.com/2011/09/autism-news-genetics-of-autism-spectrum-disorders/" style="margin-left: 1em; margin-right: 1em;"><img alt="http://ultimateautismguide.com/2011/09/autism-news-genetics-of-autism-spectrum-disorders/" border="0" src="http://3.bp.blogspot.com/-AZ0LPRhbTVA/VEPd_dmjNXI/AAAAAAAAAoU/rVOqBJYFdi0/s1600/genetic%2Bmutations%2Bin%2Bautism.jpg" height="288" width="400" /></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">It is worth emphasising that point: doctors and clinical geneticists can now ascribe a specific genetic cause to perhaps a quarter of individual autism patients. This is a vast increase from even a few years ago and new risk loci are being discovered at an ever-increasing rate. There is every reason to think we are only at the beginning of these discoveries as we have really just begun to look. Again, regardless of how many cases we have explained currently, the very high heritability of autism remains a fact – the important factors in the vast majority of the remaining cases will still be genetic. Far from being a failure, modern genetics has been extraordinarily successful at uncovering specific causes of autism. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">Autism can be genetic, but not inherited</span></b></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.dailymail.co.uk/health/article-2125128/Is-autism-children-mutation-sperm-eggs-older-fathers.html" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://www.dailymail.co.uk/health/article-2125128/Is-autism-children-mutation-sperm-eggs-older-fathers.html" border="0" src="http://3.bp.blogspot.com/-N9QCo0xgMnU/VEPeZzI6TxI/AAAAAAAAAoc/XLOuZjMLNM8/s1600/sperm%2Band%2Beggs.jpg" height="216" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">One common objection to the idea that autism is a genetic condition is that so many cases of autism are sporadic – they occur in a family where no one else has autism. How could it be the case that the condition is <i style="mso-bidi-font-style: normal;">genetic</i> if it is apparently not <i style="mso-bidi-font-style: normal;">inherited</i>? This situation can arise when the condition is caused by a new mutation – a change in the DNA that occurs in the generation of sperm or egg cells (mostly sperm, as it happens). These occur all the time – this is how genetic variation enters the population. Most of the time these “<a href="http://ghr.nlm.nih.gov/glossary=denovomutation"><i style="mso-bidi-font-style: normal;">de novo</i></a>” mutations have no effect, but sometimes they disrupt an important gene and can result in disease. When they disrupt one of the many hundreds of genes important for brain development, they can result in autism.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">It has been estimated that as many as half of all autism cases are <a href="http://www.ncbi.nlm.nih.gov/pubmed/24430941">caused by de novo mutations</a>. By comparing the sequence of an affected child’s genome with that of their parents it is possible to tell whether a mutation was inherited or arose <i style="mso-bidi-font-style: normal;">de novo</i>. This is obviously important information in assessing the risk in that family to future offspring – in the case of a <i style="mso-bidi-font-style: normal;">de novo</i>mutation, this should not be higher than the population baseline risk. By contrast, if the mutation was inherited, then risk to subsequent children may approach 50%.</span><span lang="EN-GB"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">Another important finding is that the effects of such mutations are more severe in males than in females. Not all carriers of the known disease-linked mutations actually develop autism. Some develop other disorders, while some are apparently healthy and unaffected (or at least have no clinical diagnosis). This means people can be carriers of such a mutation but not have autism themselves. This is especially <a href="http://www.ncbi.nlm.nih.gov/pubmed/24581740">true for females</a>. In cases where a pathogenic mutation in an autism patient was inherited from an unaffected parent, that parent is twice as likely to be the mother as the father. Also, the mutations observed in female patients who do have a diagnosis of autism tend to be much more severe than those observed in male patients. These data are consistent with a model where the male brain is more susceptible to the effects of autism-causing mutations than the female brain. This can explain why an apparently unaffected couple can have multiple children with autism. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">These genetic findings also highlight a fundamental point: autism is not a single condition. The clinical heterogeneity has always been acknowledged (leading to the use of the term autism spectrum disorder), but it is now also clear that is also extremely heterogeneous from an etiological point of view. Autism is really an umbrella term – it refers to a set of symptoms that can arise as a consequence of probably hundreds of distinct genetic conditions. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">Defining new genetic syndromes</span></b></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">Those distinct conditions were never obvious before, because we had no way to distinguish between people who carry mutations in different genes. But now genomic technologies can identify people with the same mutations and are allowing clinicians to define new syndromes, which may be characterised by a typical profile of symptoms. For example, mutations in a gene called <i style="mso-bidi-font-style: normal;">CHD8</i> are a newly discovered, very rare cause of autism, but enough cases have now been studied to <a href="http://www.ncbi.nlm.nih.gov/pubmed/24998929">define a symptom profile</a>, showing for example that these patients are at especially high risk of co-morbid gastrointestinal problems (found at higher rate in autism generally, but not in all cases). Knowing the cause in individuals can thus provide important information on prognosis, common co-morbidities, even responsiveness to medications. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://en.wikipedia.org/wiki/File:Genetictesting.png" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://en.wikipedia.org/wiki/File:Genetictesting.png" border="0" src="http://2.bp.blogspot.com/-ORwfF09Tka0/VEPfbnw-7AI/AAAAAAAAAoo/F4VEkXZlgU4/s1600/genetic%2Btesting.jpg" height="213" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">The application of genetic testing in cases of autism should spare many children and parents the diagnostic odyssey that many currently suffer through. A definitive diagnosis can bring important benefits in terms of how families think of and deal with the </span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">condition. Indeed, support groups have arisen for many rare genomic disorders, allowing parents to compare experiences with other families with the same condition. On the other hand, as described in a <a href="http://www.ncbi.nlm.nih.gov/pubmed/20964600">recent review </a>on this topic: “</span><i style="mso-bidi-font-style: normal;"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">we should balance our enthusiasm</span></i><i style="mso-bidi-font-style: normal;"><span style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"></span></i><i style="mso-bidi-font-style: normal;"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">for finding a genetic diagnosis with the recognition that autistic</span></i><i style="mso-bidi-font-style: normal;"><span style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"></span></i><i style="mso-bidi-font-style: normal;"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">traits represent one aspect of a diverse behavioral spectrum, and</span></i><i style="mso-bidi-font-style: normal;"><span style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"></span></i><i style="mso-bidi-font-style: normal;"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">work to avoid any potential stigmatization of the patient and</span></i><i style="mso-bidi-font-style: normal;"><span style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"></span></i><i style="mso-bidi-font-style: normal;"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">family through identification of genetic susceptibility</span></i><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">”.</span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">The use of genetic information in clinical management is likely to become increasingly important in</span><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;"> the near future as we learn more about newly discovered syndromes and their underlying biology. This kind of personalised medicine is already happening in other fields, such as oncology. One can hope that its application in psychiatry will go a long way towards transforming the experiences in the health service of autism patients and their parents and reducing the frustrations that arose when we were effectively operating in the dark. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">This is a positive message of real success in science that is already changing how we think about disorders like autism and that is likely to completely transform the practice of psychiatry, especially for neurodevelopmental disorders. Scientists need to do a better job of getting that truth out there. <span style="mso-spacerun: yes;">&nbsp;</span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">*(For the record, I declare no such conflicts myself). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;">&nbsp;Thanks to Dorothy Bishop, Svetlana Molchanova and Emily Willingham for helpful comments on this post.</span></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;"><br /></span></div><div class="MsoNormal"><span lang="EN-GB" style="mso-ascii-font-family: Cambria; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-font-family: Cambria;"><br /></span></div></div>http://www.wiringthebrain.com/2014/10/autism-truth-is-not-out-there.htmlnoreply@blogger.com (Kevin Mitchell)7tag:blogger.com,1999:blog-6146376483374589779.post-7822073080291906980Tue, 22 Jul 2014 12:01:00 +00002014-07-23T00:58:51.643-07:00common variantsgenetic architectureGWASrare variantsschizophreniaExciting findings in schizophrenia genetics – but what do they mean? <div dir="ltr" style="text-align: left;" trbidi="on"><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style></div>--&gt; <div class="MsoNormal"><span lang="EN-GB"></span><span lang="EN-GB"></span><span lang="EN-GB">A <a href="http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13595.html">paper published today</a> represents a true landmark in psychiatric genetics. It reports results of a genome-wide association study (GWAS) of schizophrenia, involving </span><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">36,989 cases and 113,075 controls. Assembling this sample required collaboration on a massive scale, with over 300 authors involved. This huge sample gives unprecedented statistical power to detect genetic variants that predispose to disease, even if their individual effects on risk are tiny. The study reports 108 regions of the genome where genetic differences affect risk of disease. This achievement is rightly being widely celebrated and reported, but what do these results really mean?</span> </div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;"><a href="http://en.wikipedia.org/wiki/Genome-wide_association_study">GWAS</a> look at sites in the genome where the particular base in the DNA sequence is variable – it might sometimes be an “A”, other times a “T”, for example. There are millions of such sites in the human genome (which comprises over 3 billion bases of sequence). Each <a href="http://en.wikipedia.org/wiki/Single-nucleotide_polymorphisms">such site</a> represents a mutation that happened some time in the distant past, which has since been inherited and spread throughout the population, while not supplanting the previous version completely. This leaves some people with one version and some with another – these different versions are thus called “common variants”. [More correctly, since we each have two copies of each chromosome, each of us carries two copies of each variable site, so the combined genotype could be AA, AT or TT, in the example above]. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">The idea of a GWAS is to look across the entire genome at over a million such variants for ones at higher frequency in disease cases than in controls. That difference in frequency might be very minor (say, the “A” version might be seen at a frequency of 30% in cases but 27% in controls), but with such a huge sample size, that kind of variation can be statistically significant. In epidemiological terms, the variant that is more common in cases is termed a “risk factor” – if you have it, you are statistically more likely to be in the case group than in the control group. (Just as smoking is more common in people with lung cancer than in people without, although in that case the difference in frequency is massive). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">For any individual common variant, the increased statistical risk is tiny – most increase risk by less than 1.1-fold. But the idea is that the combined risk associated with a large number of such variants could be quite large – large enough to push people into disease. Since the variants are common, each of us will carry many of them, but some people will carry more than others. This will generate a distribution of “risk variant burden” across the population. If there are 108 sites, each in two copies, then the range of that distribution could theoretically be from 0 to 216 risk variants. The actual distribution is far narrower however, with the vast majority of the population carrying somewhere between 90 and 130 risk variants (assuming the relative frequencies of the two variants are around 50:50, on average). </span></div><div class="separator" style="clear: both; text-align: center;"><a href="http://1.bp.blogspot.com/-NxAqZNCFO0w/U85PUr2Kv3I/AAAAAAAAAm0/S6i9YyZ2Ypg/s1600/Binomial,+n=108+loci.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://1.bp.blogspot.com/-NxAqZNCFO0w/U85PUr2Kv3I/AAAAAAAAAm0/S6i9YyZ2Ypg/s1600/Binomial,+n=108+loci.jpg" height="225" width="400" /></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">One way to conceptualise the combined effects of many variants is the “liability-threshold” model, which suggests that though there is a smooth distribution of genetic burden (or liability) across the population, only those above a certain threshold become ill (say the top 1% in the case of schizophrenia). This is known as a polygenic model of risk because it assumes the causal action of a large number of genes in any individual. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">An <a href="http://www.ncbi.nlm.nih.gov/pubmed/20380786">alternative model</a> views common disorders such as schizophrenia as arising mainly due to very rare mutations of large effect, but in different genes in different individuals (and with the possibility of modifying effects of other variants in the genetic background). This scenario is known as genetic heterogeneity. Many such rare, high-risk mutations <a href="http://www.ncbi.nlm.nih.gov/pubmed/20832285">are known</a> but the ones we currently know about collectively account for less than 10% of cases of schizophrenia, e.g., <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=23813976">here</a> (and <a href="http://www.ncbi.nlm.nih.gov/pubmed/23425232">15</a>-<a href="http://www.ncbi.nlm.nih.gov/pubmed/21658575">30</a>% of cases of autism). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">So, with that as background, let’s consider what the GWAS signals mean, individually and collectively. First, GWAS signals are a bit like <a href="http://knowyourmeme.com/memes/greenfieldism">#Greenfieldisms</a>: they point to a locus and they point to an increased statistical risk of disease – that is all. This is because the common variant that is interrogated is being used as a tag of wider genetic variation at that locus (a locus is just a small region of the genome). Chromosomes tend to be inherited in large chunks without too much mixing (or recombination) between the two copies present in each parent. That means that one common variant at one position will tend to be co-inherited with other common variants nearby. The signal derived from GWAS is associated with one of those (or sometimes several), but tags a lot of additional variation. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">Generally, the presumption is that one of the common variants is having a causal effect and the others are merely passengers. However, there are also lots of rare mutations that come along for the ride. These are mutations that arose much more recently and that are therefore present in far fewer individuals. Though GWAS can’t see them directly, any such mutation necessarily arises on the background of a particular set of common variants (called a haplotype). Most people with that haplotype will not carry the rare mutation, but it may be possible that several such mutations in the population (if they are of large effect and thus found mainly in cases) can give an aggregate signal that boosts the frequency of the common haplotype in cases, resulting in a GWAS signal (driven by a “<a href="http://www.ncbi.nlm.nih.gov/pubmed/20126254">synthetic association</a>”). Several examples of such cases are now found in the literature, for other conditions (e.g., <a href="http://www.ncbi.nlm.nih.gov/pubmed/24550738">1</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/23990791">2</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/23615072">3</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/22968135">4</a>), though it is not clear if synthetic associations drive any of the signals in the most recent schizophrenia study. </span></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.ncbi.nlm.nih.gov/pubmed/22269335"><img alt="http://www.ncbi.nlm.nih.gov/pubmed/22269335" border="0" src="http://2.bp.blogspot.com/-q0wPtMWvTpU/U85RHCn9kNI/AAAAAAAAAnA/3g9KgoZ7mNw/s1600/GWAS+signals.jpg" height="377" width="400" /></a></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;"><br /></span></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">It is striking, however, that many of the loci implicated by GWAS signals are known to sometimes carry rare mutations that dramatically increase risk of disease. Some of the 108 loci implicated contain only one gene, but some encompass many, while others have no gene in the region or even nearby. Cases where the implicated gene is clear include genes like <i style="mso-bidi-font-style: normal;">TCF4, CACNA1C, CACNB2, CNTN4, NLGN4X </i>and multiple others, where rare mutations are known to cause specific genetic syndromes. Moreover, there is substantial enrichment in the GWAS loci for genes in which rare mutations have been discovered in cases with schizophrenia, autism or intellectual disability (including <i style="mso-bidi-font-style: normal;">CACNA1I, GRIN2A LRP1, RIMS1</i> and many others). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">These findings strongly reinforce the validity of the GWAS results and also suggest that many of the loci identified sometimes carry rare, high-risk mutations that should be very informative for follow-up mechanistic studies. Whether the GWAS signals themselves are driven by such rare mutations in the samples under study is an open question. (<a href="http://journals.lww.com/psychgenetics/Citation/publishahead/The_functional_GRM3_Kozak_sequence_variant.99701.aspx">Another paper</a>just out suggests that signals from the <i>GRM3</i> locus, which encodes a metabotropic glutamate receptor, may be driven by a rare variant that increases risk of mental illness generally by about 2.7-fold). But there are also many examples of loci where both rare and common variation is known to play a role in disease risk and the GWAS signal could well be driven purely by common variants with direct functional effects. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">However, such effects need not be tiny in individuals, even if their overall signal of increased risk across the population is very small. We know of many examples of common variants that strongly modify the effects of rare mutations, at the same locus or at one encoding an interacting protein. In such cases, the common variant may increase risk of expression of a disorder due to a rare mutation, but essentially have no effect in most of the population who do not carry such a rare mutation. This situation is exemplified by <a href="http://en.wikipedia.org/wiki/Hirschsprung%27s_disease">Hirschsprung’s disease</a>, a condition affecting innervation of the gut. It can be <a href="http://www.ncbi.nlm.nih.gov/pubmed/23707863">caused by</a> rare mutations in any of 18 known genes. However, such mutations do not always cause disease and the range of severity is also very wide. Common variants at several of those same risk loci have been found to be much more frequent in people with rare mutations who develop disease than in those with the same mutations who remain healthy. When averaged across the population, as in a GWAS study, such effects would yield only a tiny average increase in risk, but this may reflect a large effect in a small subset of people and no effect in the majority.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">This brings us to a larger point – what do the GWAS signals tell us collectively? More specifically, should they be taken as evidence in support of a polygenic model of disease risk, where it is the collective burden of common risk variants that causes the majority of disease cases? </span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">One way to test that is to model the variance of the “liability” to the disease, which is actually an unmeasurable parameter, but which is assumed to be normally distributed in the population. With that and a number of other assumptions in place, one can then ask how much of the variance in this trait is accounted for by the loci identified by the GWAS? The authors state that a combined risk profile score “<i style="mso-bidi-font-style: normal;">now explains about 7% of variation on the liability scale to schizophrenia across the samples</i>”. That is an improvement over previous studies (the first 13 loci accounted for about 3%), but certainly not as much as might have been expected under a purely polygenic model. Of course, it could just be that only a fraction of the contributing common variants have been found and that larger studies would identify more.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">However, the GWAS data are also fully consistent with a more <a href="http://genomebiology.com/2012/13/1/237">complex model</a> of genetic heterogeneity, which involves common variants interacting with rare variants to determine individual risk. Population averages of their effects remain just that – statistical measures that cannot be applied to individuals. Even combining all the common variants to generate a risk profile score does not generate a predictive measure of risk for individuals. (One reason for that is that non-additive genetic interactions that are likely highly important in individuals are averaged out by population-level signals). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">So, the current study points the finger at a large set of new genes, but does not really discriminate between models of genetic architecture. The overlap between the GWAS signals and the genes known to carry rare, high-risk mutations certainly suggests that the GWAS has been successful in identifying important risk loci - a tremendous advance for which the authors should be congratulated (as well as for their willingness to collaborate on this level). This is, however, just a first step in understanding the biology of the disease. The underlying genetic heterogeneity presents a tremendous challenge but also an opportunity, as individual high-risk mutations can be followed up in functional studies to elucidate some of the mechanisms through which a change in some piece of DNA can ultimately produce the particular psychological symptoms of this often-devastating disease.</span></div><br />http://www.wiringthebrain.com/2014/07/exciting-findings-in-schizophrenia.htmlnoreply@blogger.com (Kevin Mitchell)0tag:blogger.com,1999:blog-6146376483374589779.post-583109389524571331Tue, 08 Jul 2014 15:26:00 +00002014-07-08T08:26:55.229-07:00autismclinical geneticsepilepsygeneticsheterogeneityrare disordersrare mutationsschizophrenia"Common disorders" are really collections of rare genetic conditions<div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; mso-themecolor:hyperlink; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> <br /><span lang="EN-GB">Disorders such as autism, schizophrenia and epilepsy each affect about 1% of the population and are therefore defined as “common disorders”. But are they really? I mean, they are clearly really that common, but are they really “disorders”? Are they natural categories that reflect some shared underlying etiology or are they simply groupings based on sets of shared symptoms? Genetics is providing an answer to that question and demonstrating that so-called “common disorders” are really collections of rare disorders with similar symptoms. This represents a complete paradigm shift in psychiatry, the full ramifications of which have yet to be appreciated. </span> <div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://directorsblog.nih.gov/2014/01/28/exploring-the-complex-genetics-of-schizophrenia/" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://directorsblog.nih.gov/2014/01/28/exploring-the-complex-genetics-of-schizophrenia/" border="0" src="http://4.bp.blogspot.com/-Os14ba-jH9c/U7wMzguA0HI/AAAAAAAAAmU/9tLLouBqM8U/s1600/Genes+brain.jpg" height="283" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">We have known for decades of examples of rare genetic syndromes that can include symptoms of autism spectrum disorder (such as <a href="http://en.wikipedia.org/wiki/Fragile_X_syndrome">Fragile X syndrome</a> or <a href="http://en.wikipedia.org/wiki/Rett_syndrome">Rett syndrome</a>) or of schizophrenia (such as <a href="http://en.wikipedia.org/wiki/DiGeorge_syndrome">velo-cardio facial syndrome</a>, now called 22q11 deletion syndrome), while epilepsy is a known symptom of many genomic disorders. But such examples were typically thought of as exceptional and distinct from the much larger group of idiopathic cases of ASD, SZ or epilepsy. (<a href="http://en.wikipedia.org/wiki/Idiopathic">Idiopathic</a> simply means of currently unknown cause). Such conditions were often dismissed as not “real autism” or “real schizophrenia”, despite the fact that clinicians could not make any such assessment based on symptoms alone. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Instead, it was widely held to be a proven fact that the genetics of ASD and SZ generally followed a very different mode – rather than being caused by single mutations, as with the syndromes mentioned above, the idea was that the idiopathic cases were caused by combinations of tens or hundreds (or even thousands) of minor genetic differences, each with only a tiny effect on its own, but <a href="http://en.wikipedia.org/wiki/Common_disease-common_variant">collectively sufficient </a>to result in disease if enough of them were inherited. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Modern genomic technologies are revealing that this supposed dichotomy between rare and common disorders is artificial – merely a reflection of our current state of knowledge (or, more correctly, our current state of ignorance). Over the past five years, researchers have discovered many more rare genetic conditions that manifest with psychiatric symptoms, and which collectively can account for an ever-growing percentage of patients presenting with ASD or SZ. These include <a href="http://en.wikipedia.org/wiki/Copy-number_variation">deletions or duplications</a> of whole chunks of chromosomes, often affecting many genes, as well as mutations that affect only one gene. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.123rf.com/photo_4981342_a-cassette-tape-has-been-destroyed-and-the-tape-unraveled.html" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.123rf.com/photo_4981342_a-cassette-tape-has-been-destroyed-and-the-tape-unraveled.html" border="0" src="http://3.bp.blogspot.com/-wT1O9Md36IA/U7wNYR3hNII/AAAAAAAAAmc/izyT5k3CTVY/s1600/cassette+tape.jpg" height="234" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">[The DNA sequence of each gene codes for production of a specific protein. Genes are strung along chromosomes, like the information encoding successive songs on a cassette tape. (I may be showing my age with this reference!) Localised damage to the tape at one specific point can affect just one song, but cutting out a whole section could remove or disrupt multiple songs at the same time. Similarly, changing one letter of the DNA sequence can alter the code for a single protein, while deleting a whole section of chromosome can remove multiple genes and thereby affect production of multiple proteins at once].</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Some regions of the genome are particularly prone to errors in DNA replication that result in deletions or duplications. While still rare, these recur at a high enough frequency that many cases with effectively the same genetic lesion can be identified. This has enabled researchers to recognise and characterise a growing number of genomic disorders that carry a high risk of psychiatric or neurological symptoms. In addition to previously known conditions such as 22q11 deletion syndrome, Williams, Angelman and Prader-Willi syndromes, new conditions have been defined involving deletions or duplication at 1q21.1, 3q29, 7q36.2, 15q11.2, 16p11.2, 22q13 and many others, with more being recognised all the time. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">All of these mutations have <a href="http://www.ncbi.nlm.nih.gov/pubmed/23992924">variable effects</a>, sometimes presenting as ASD, sometimes as SZ or epilepsy – often, but not always, with developmental delay or intellectual disability. Because their clinical manifestations are so variable, there was no way to detect or recognise these patients prior to genetic screening (except for conditions with other characteristic symptoms, such as distinct facial morphology). But once a genetic diagnosis can be made, it becomes possible to group patients with the same mutation together and determine whether there are any patterns to their symptoms, their course of illness, how they respond to medications, and other clinical parameters. This is useful information for clinicians and also for patients and their families – indeed, <a href="http://www.rarechromo.org/html/home.asp">international support groups</a> have been formed for many of these rare genomic conditions.<span style="mso-spacerun: yes;">&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;</span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">New conditions caused by mutations in specific genes are also being defined. Rett syndrome is a classic example – a form of autism and intellectual disability in girls that is caused by mutations in a gene called <a href="http://en.wikipedia.org/wiki/MECP2"><i style="mso-bidi-font-style: normal;">MeCP2</i></a>. New genomic sequencing technologies are now revealing many more such conditions, although the pace of discovery here has been slower, for two reasons. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">First, if you sequence the entire genome of any individual you will find many serious mutations – severely affecting production or function of a <a href="http://www.ncbi.nlm.nih.gov/pubmed/22344438">couple hundred</a> proteins (out of ~20,000 in total). Recognising which one of those is causing disease in a particular patient is impossible, unless you have some prior information. That information can come from seeing the same gene mutated in multiple patients with a particular condition. That brings up the second problem – the number of genes in which mutations can cause ASD or SZ or epilepsy is very large, probably on the order of a thousand. So the likelihood that any two patients will have a mutation in the same gene is very low. This means we will need to sequence very large samples of patients to start to see the signal of meaningful repeat hits amongst the background noise of repeats that arise by chance, simply because we all carry many mutations. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Those efforts are underway and are beginning to pay off, with new conditions being defined at an ever-increasing rate. One recent example involves mutations in the gene <a href="http://www.ncbi.nlm.nih.gov/pubmed/24998929"><i style="mso-bidi-font-style: normal;">CHD8</i></a>. Mutations that disrupt this gene have been observed in multiple patients with diagnoses of developmental delay or ASD (15 independent mutations in 3,730 cases), but never in a sample of 8,792 clinically unaffected controls. You can see how rare these mutations are – accounting for only 4 of every 1000 cases – but the fact that you don’t see such mutations in controls provides strong evidence that they are in fact the cause of disease in those patients. (See <a href="http://www.wiringthebrain.com/2014/01/on-genetic-causality-forwards-and.html">here</a> for a much more nuanced discussion of causality in genetic disorders – the phenotypic effects of any single mutation will always be modified, sometimes strongly, by additional genetic variants in the background).<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">By finding multiple patients with mutations in the same gene, clinicians were able to define a new syndrome that was previously unrecognisable. In this case, patients with <i style="mso-bidi-font-style: normal;">CHD8</i> mutations display <a href="http://en.wikipedia.org/wiki/Macrocephaly">macrocephaly</a> (increased head size), distinct faces and gastrointestinal problems (the CHD8 protein has independent functions in both the brain and the nervous system innervating the gut). The genetic information is thus directly and immediately relevant to the clinical management and treatment of these cases. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now, one might say that such mutations are so rare that they don’t really tell us anything about the generality of conditions like ASD or SZ. But the point is, there is no reason to think such a thing exists. As more and more mutations causing high risk of psychiatric conditions are discovered, the percentage of cases remaining idiopathic decreases. Those diagnostic categories are not founded on knowledge but on ignorance of underlying cause, by definition. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Known, high-risk mutations can now be identified in &gt;10% of cases of SZ, 25-30% of cases of ASD, and over 60% of cases of severe intellectual disability. Those numbers represent a vast increase from even a few years ago and are sure to increase rapidly in the very near future. Even if the genetic effects in many cases are more complicated (involving more than one mutation at a time, with contributions from common variants), the major message remains the same: these conditions are incredibly genetically heterogeneous. It is probably far more appropriate to think of “autistic symptoms” or “schizophrenic symptoms” as a common consequence of many distinct genetic conditions, than to think of “autism” or “schizophrenia” as monolithic disorders. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">That has hugely important implications not just for clinical practice but also for research. If you take a hundred patients with ASD, you might have 70-80 distinct genetic causes. That’s something to consider in the context of, say, neuroimaging studies that look for commonalities across groups of ASD or SZ patients. Any time I see a study reporting some difference in brain structure “in autism” or “in schizophrenia”, I replace that phrase with “in intellectual disability” and see if it still makes any sense. (It doesn’t, give the well-accepted heterogeneity of ID). Of course, there may be some commonalities in the final outcome in these patients, given they end up with similar symptoms, but research purporting to look at causes should bear the genetic heterogeneity in mind.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Genetics is increasingly providing the means to distinguish the underlying causes in different patients and hopefully develop a far more personalised approach to care. Fortunately, <a href="http://en.wikipedia.org/wiki/CRISPR/Cas_system">new technologies</a>of genome editing are making it much easier to recapitulate disease-causing mutations in animals so that pathogenic mechanisms can be elucidated. Just in the past couple weeks, very exciting results have been published that help localise the primary effects of particular mutations (in the genes <a href="http://www.ncbi.nlm.nih.gov/pubmed/24945774"><i style="mso-bidi-font-style: normal;">SYNGAP1</i></a> and <a href="http://www.cell.com/cell/abstract/S0092-8674%2814%2900673-4"><i style="mso-bidi-font-style: normal;">NLGN3</i></a>) to specific cell types in specific regions of the developing brain in mouse models.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The recognition that these common diagnostic categories are really collections of very rare conditions will necessitate a shift in approaches aimed at developing new treatments. The <a href="http://informahealthcare.com/doi/abs/10.1517/21678707.2014.924850?src=recsys">economics of drug development</a> for rare conditions are obviously very different from the search for the new blockbuster. The next big challenge is to elucidate the biological mechanisms leading to disease across many different mutations to determine if there are any shared pathways or common pathophysiological endpoints that might be targeted in large groups of patients or if individualised treatments can be (or need to be) developed for very small and specific sets of patients, as is happening in other areas of medicine. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB"><br /></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2014/07/common-disorders-are-really-collections.htmlnoreply@blogger.com (Kevin Mitchell)7tag:blogger.com,1999:blog-6146376483374589779.post-8939626726658990426Mon, 14 Apr 2014 19:54:00 +00002014-04-14T12:54:37.146-07:00behaviourbullshitepigeneticsinheritancereal geneticsThe Trouble with Epigenetics, Part 3 – over-fitting the noise<div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} @font-face {font-family:"Trade Gothic LT Std Light"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-alt:Cambria; mso-font-charset:77; mso-generic-font-family:swiss; mso-font-format:other; mso-font-pitch:auto; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:"Trade Gothic LT Std"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-alt:"Trade Gothic LT Std"; mso-font-charset:77; mso-generic-font-family:swiss; mso-font-format:other; mso-font-pitch:auto; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.Default, li.Default, div.Default {mso-style-name:Default; mso-style-unhide:no; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:none; mso-layout-grid-align:none; text-autospace:none; font-size:12.0pt; font-family:"Trade Gothic LT Std Light","sans-serif"; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-bidi-font-family:"Trade Gothic LT Std Light"; color:black;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> <br /><div class="MsoNormal"><span lang="EN-GB"></span><span lang="EN-GB"></span><span lang="EN-GB">The idea of transgenerational epigenetic inheritance of acquired behaviors is in the news again, this time thanks to a <a href="http://www.nature.com/neuro/journal/vaop/ncurrent/abs/nn.3695.html">new paper</a> in Nature Neuroscience (who seem to have a liking for this sort of thing).</span> </div><div class="MsoNormal"><br /></div><div class="Default">The paper is provocatively titled: <span style="mso-spacerun: yes;">&nbsp;</span>“<b style="mso-bidi-font-weight: normal;">Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice</b>”. The abstract claims that:</div><div class="Default"><br /></div><div class="Default"><span style="font-size: small;">“<b><span style="font-family: &quot;Trade Gothic LT Std&quot;,&quot;sans-serif&quot;;">We found that traumatic stress in early life altered mouse microRNA (miRNA) expression, and behavioral and metabolic responses in the progeny. Injection of sperm RNAs from traumatized males into fertilized wild-type oocytes reproduced the behavioral and metabolic alterations in the resulting offspring.”</span></b></span><span style="font-family: &quot;Trade Gothic LT Std&quot;,&quot;sans-serif&quot;; mso-bidi-font-family: &quot;Trade Gothic LT Std&quot;;"></span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://2.bp.blogspot.com/-4luQeMviXA0/U0w5s5_5cwI/AAAAAAAAAkc/kcM7hm3NtDU/s1600/Darwin+in+cloud.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" src="http://2.bp.blogspot.com/-4luQeMviXA0/U0w5s5_5cwI/AAAAAAAAAkc/kcM7hm3NtDU/s1600/Darwin+in+cloud.jpg" height="213" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">Unfortunately, the paper provides no evidence to back up those extraordinary claims. It is, regrettably, a prime example of over-fitting the noise. That is, finding patterns in a mass of messy data, like faces in clouds, and building hypotheses on them after the fact. If any change in any parameter will do, it isn’t hard to find support that “something happens”. I have <a href="http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-2.html">written about this problem</a> before, exemplified by previous papers from this group. I normally try not to be sarcastic here, but I don’t have time to edit today, so you’re getting raw, unfiltered exasperation this time. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There are some documented examples of transgenerational effects mediated by RNAs in sperm, especially in worms and plants. Almost all of these involve repression of transposon or transgene insertions. This is not believed to be a widespread phenomenon in mammals, however, and you don’t need to (and shouldn’t!) take my word for it – the following is from a very <a href="http://www.cell.com/cell/abstract/S0092-8674%2814%2900286-4">recent review</a> by leaders in this field:</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="font-size: small;"><span style="font-family: &quot;Times New Roman&quot;;">"...epigenetic inheritance is usually—if not always—associated with transposable elements, viruses, or transgenes and may be a byproduct of aggressive germline defense strategies. In mammals, epialleles can also be found but are extremely rare, presumably due to robust germline reprogramming. How epialleles arise in nature is still an open question, but environmentally induced epigenetic changes are rarely transgenerationally inherited, let alone adaptive, even in plants. Thus, although much attention has been drawn to the potential implications of transgenerational inheritance for human health, so far there is little support."</span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Shutting down a transposon in gametes and the resultant offspring is one thing – it’s a pretty straightforward molecular mechanism, actually. Using such a mechanism to transmit a behavioural change induced by an experience in the previous generation is something else entirely. What that would require is the following sequence of events: animal has an experience, experience is registered by the brain (so far, so good), signal is transmitted to the gametes (hmm, by what?), relevant gene or genes are specifically modified (how? why just those genes?), modification is maintained in the zygote through “genome rebooting” (what, now?), modification is maintained throughout subsequent development of the animal and the brain (really?), but in a selective way so that somehow in the adult it only affects expression in certain brain regions so as to initiate an appropriate behavioural change in the offspring (ah, c’mon, now you’re taking the piss...). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">That is why my skepticometer gets pegged by studies that make such claims without documenting or even suggesting a plausible mechanism by which such events could occur. The current paper takes a stab at one part of that, by looking at small non-coding RNAs as a possible mediator. Unfortunately, the paper is… well, let me show you.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The authors use a paradigm which they developed previously (in one of the <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=20673872">papers</a> which I criticised <a href="http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-2.html">here</a>), to induce what they call a traumatic stress. This involves “</span><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">unpredictable maternal separation combined with unpredictable maternal stress (MSUS) for 3 hours daily from postnatal day 1 through 14 (PND 1–14)”. The pups don’t like that, apparently, and the authors claim they grow up to show “depressive-like behaviours”. I find those behavioural data a bit shaky, but they get much worse in the following generations, when the responses vary in one test, in one sex in one generation and then in another test in the other sex in the next. It all looks like noise to me, and, the authors neither correct for all these multiple tests, nor provide any hypothesis to account for these fluctuating effects. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">In their 2010 paper, they looked at DNA methylation of some candidate genes in F1 sperm and F2 brains to see if they could find a molecular mechanism. Here’s the figure:</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://2.bp.blogspot.com/-k51ur2nDCIw/U0w6QSroXOI/AAAAAAAAAkk/kOVBfhFrebc/s1600/Screen+Shot+2014-04-14+at+7.47.22+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://2.bp.blogspot.com/-k51ur2nDCIw/U0w6QSroXOI/AAAAAAAAAkk/kOVBfhFrebc/s1600/Screen+Shot+2014-04-14+at+7.47.22+PM.png" height="640" width="465" /></a></div><br /> <div class="MsoNormal"><br /></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;"></span><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;"></span><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;"></span><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">There are a lot of asterisks on there, indicating some changes that are statistically significant (alone), but you’ll notice how many different measurements they have made and, also, I hope, the lack of consistency in the supposed effects from F1 to F2. Importantly, there is no independent replication – just one big experiment with the stats done on the whole lot at once. It is no surprise that some data points come out as significant. I’m thinking of <a href="http://xkcd.com/882/">green jelly beans</a>… </span> </div><div class="MsoNormal"><br /></div><div class="Default">You can see the same kind of thing in the figure <span style="font-family: Cambria; mso-ascii-theme-font: minor-latin; mso-hansi-theme-font: minor-latin;">below from this <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=24292232">recent paper</a>, which also got a lot of media attention: “</span><b><span style="font-family: Cambria; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: &quot;Trade Gothic LT Std&quot;; mso-hansi-theme-font: minor-latin;">Parental olfactory experience influences behavior and neural structure in subsequent generations”</span></b><span style="font-family: Cambria; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: &quot;Trade Gothic LT Std&quot;; mso-hansi-theme-font: minor-latin;"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://4.bp.blogspot.com/-dQPiKd9lqn8/U0w6vwx7oqI/AAAAAAAAAks/TZuptbTXT1w/s1600/Screen+Shot+2014-04-14+at+7.51.27+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-dQPiKd9lqn8/U0w6vwx7oqI/AAAAAAAAAks/TZuptbTXT1w/s1600/Screen+Shot+2014-04-14+at+7.51.27+PM.png" height="640" width="486" /></a></div><br /> <div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In both cases, the data look to me like noise. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now, back to this latest paper. Amidst a load of somewhat peripheral data, the data supporting the two main claims of the paper are the following: First, the authors claim that the maternal separation protocol alters the levels of various small non-coding RNA molecules in the sperm of the F1 mice (the ones whose moms were cruelly taken away). The data for that claim are in Supplemental Figure 2, which I reproduce below. You will see it derives from three pools of mice for the control condition and three pools from the MSUS condition.</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://4.bp.blogspot.com/-nOH5nh1skww/U0w67s-i71I/AAAAAAAAAk0/W_a740Ipv4o/s1600/Screen+Shot+2014-04-14+at+7.55.34+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-nOH5nh1skww/U0w67s-i71I/AAAAAAAAAk0/W_a740Ipv4o/s1600/Screen+Shot+2014-04-14+at+7.55.34+PM.png" height="640" width="496" /></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">&nbsp;</span><span lang="EN-GB">I see no consistent pattern of changes here. There looks to be as much variability within conditions as between. (Take MSUS pool 2 out and you wouldn’t be left with much signal, I would wager). I am sure there is some statistical test that would give you a significant result, but if you torture the data enough, they’re bound to try to tell you something. </span> </div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Their next figure takes some of these specific miRNAs and examines their expression levels in sperm, serum and various brain regions of F1 and F2 mice. Again, the data are all over the place. They’re up, they’re down, they’re not changed. They’re changed in hippocampus but some go in the opposite direction in hypothalamus and none are changed in cortex (Supplementary Figure 10 for those reading along at home). </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://4.bp.blogspot.com/-sb4R9hvwq2M/U0w7Lx-2pGI/AAAAAAAAAk8/dINGQOQdIfM/s1600/Screen+Shot+2014-04-14+at+8.00.41+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-sb4R9hvwq2M/U0w7Lx-2pGI/AAAAAAAAAk8/dINGQOQdIfM/s1600/Screen+Shot+2014-04-14+at+8.00.41+PM.png" height="348" width="640" /></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB"></span><span lang="EN-GB">That’s some noisy noise right there. Notably, they see no changes in sperm of F2, even though the F3 supposedly still show behavioural changes, rather undermining their own case for the link between these two (non-)events. </span> </div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Their next step is the one that the main conclusion rests on – to show that injection of small RNAs from the sperm of an MSUS F1 mouse into a fertilised oocyte can induce the suite of behavioural changes they (claim to) see in the F2 generation under normal conditions. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Amazingly, they do not actually show those data. We get summary <i style="mso-bidi-font-style: normal;">t</i> statistics claiming there are some differences but are not treated to the actual data themselves. So, we can’t evaluate the effect sizes or the underlying variability of the data. Here’s how it reads in the paper:</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://4.bp.blogspot.com/-iXxALwQcyDY/U0w7XqvojwI/AAAAAAAAAlE/m3FN0VQa-eA/s1600/Screen+Shot+2014-04-14+at+8.07.39+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-iXxALwQcyDY/U0w7XqvojwI/AAAAAAAAAlE/m3FN0VQa-eA/s1600/Screen+Shot+2014-04-14+at+8.07.39+PM.png" height="310" width="640" /></a></div><div class="MsoNormal"><span lang="EN-GB"><br /></span></div><div class="MsoNormal"><span lang="EN-GB">They do show a supposed effect on metabolism in the MSUS-RNA-injected animals, which is a difference seen in one experiment with 8 animals per group in glucose levels, not at baseline, but after stress. I have no idea what’s going on here or what the hypothesis is supposed to be – are we supposed to expect greater or lower glucose? At baseline or after a stress? Whatever is happening, it’s not consistent between the F1 and the F2 in the traditional paradigm, nor between the traditional F2 and the MSUS-RNA-injected F2.&nbsp;</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://1.bp.blogspot.com/-Iy7f_L034wM/U0w8Wl2I44I/AAAAAAAAAlU/lfMpStRQqUg/s1600/Screen+Shot+2014-04-14+at+8.51.30+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://1.bp.blogspot.com/-Iy7f_L034wM/U0w8Wl2I44I/AAAAAAAAAlU/lfMpStRQqUg/s1600/Screen+Shot+2014-04-14+at+8.51.30+PM.png" height="376" width="640" /></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Finally, we are shown that the levels of one of the miRNAs differs in the hippocampus of the MSUS-RNA-injected F2. Doesn’t look very convincing to me, by itself – it’s the kind of result one might want replicated before publishing, but more to the point: Why that one? What about all the others whose levels fluctuated so happily in the figure shown above? </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://2.bp.blogspot.com/-FPz1q4EAIVA/U0w7qro5-fI/AAAAAAAAAlM/noPoXsxu3vE/s1600/Screen+Shot+2014-04-14+at+8.15.14+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://2.bp.blogspot.com/-FPz1q4EAIVA/U0w7qro5-fI/AAAAAAAAAlM/noPoXsxu3vE/s1600/Screen+Shot+2014-04-14+at+8.15.14+PM.png" height="239" width="320" /></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB"><br /></span></div><div class="MsoNormal"><span lang="EN-GB">Overall, there’s no there there. It’s all sound and fury, signifying nothing. I would give it the ultimate insult by saying it’s not even wrong, but it is. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Nevertheless, this paper is sure to be latched onto by the woo crowd who seem to think that epigenetics is some kind of magic. (Now I have that <a href="https://www.youtube.com/watch?v=NLxN0wpFoP8">Queen song</a><a href="https://www.blogger.com/null"> </a>running in my head - you're welcome). We can change our genes! They’re not our destiny! Toxins cause autism because epigenetics! Hooray!</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Evolution appears to have made us mammals very delicate creatures. If you look sideways at a mouse these days you can permanently alter its genes, it seems, along with those of its kids and grandkids. Of course, you’d think another look might change them back if they're so sensitive, but apparently not. I’m sure your genes (ooh, and brain circuits!) have been changed by reading this, for which I can only apologise. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2014/04/the-trouble-with-epigenetics-part-3.htmlnoreply@blogger.com (Kevin Mitchell)3tag:blogger.com,1999:blog-6146376483374589779.post-101137466842690448Mon, 24 Mar 2014 11:07:00 +00002014-03-24T04:07:03.930-07:00geneticshomosexualityinnatenessscreeningsexual orientationsexual preferencetwinsGay genes? Yeah, but no, well kind of… but, so what?<div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraph, li.MsoListParagraph, div.MsoListParagraph {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraphCxSpFirst, li.MsoListParagraphCxSpFirst, div.MsoListParagraphCxSpFirst {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraphCxSpMiddle, li.MsoListParagraphCxSpMiddle, div.MsoListParagraphCxSpMiddle {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraphCxSpLast, li.MsoListParagraphCxSpLast, div.MsoListParagraphCxSpLast {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} /* List Definitions */ @list l0 {mso-list-id:716469060; mso-list-type:hybrid; mso-list-template-ids:-2128595116 67698703 67698713 67698715 67698703 67698713 67698715 67698703 67698713 67698715;} @list l0:level1 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level2 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level3 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level4 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level5 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level6 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level7 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level8 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level9 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} ol {margin-bottom:0in;} ul {margin-bottom:0in;} --></style> <br /><div class="MsoNormal"><span lang="EN-GB">Sexual preference is one of the most strongly genetically determined behavioural traits we know of. A single genetic element is responsible for most of the variation in this trait across the population. Nearly all (&gt;95%) of the people who inherit this element are sexually attracted to females, while about the same proportion of people who do not inherit it are attracted to males. This attraction is innate, refractory to change and affects behaviour in stereotyped ways, shaped and constrained by cultural context. It is the commonest and strongest genetic effect on behaviour that we know of in humans (in all mammals, actually). The genetic element is of course the <a href="http://en.wikipedia.org/wiki/Y_chromosome">Y chromosome</a>. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://mathbionerd.blogspot.ie/2013/05/accessible-research-gene-survival-and.html" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://mathbionerd.blogspot.ie/2013/05/accessible-research-gene-survival-and.html" border="0" src="http://2.bp.blogspot.com/-XisOkUVw9_8/UzAOU1YSmYI/AAAAAAAAAjs/F0DvzZmJJU0/s3200/X+and+Y.jpg" height="240" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">The idea that sexual behaviour can be affected by – even largely determined by – our genes is therefore not only not outlandish, it is trivially obvious. Yet claims that differences in sexual <i style="mso-bidi-font-style: normal;">orientation</i> may have at least a partly genetic basis seem to provoke howls of scepticism and outrage from many, mostly based not on scientific arguments but political ones. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The term sexual orientation refers to whether your sexual preference matches the typical preference based on whether or not you have a Y chromosome. It is important to realise that it therefore refers to four different states, not two: (i) has Y chromosome, is attracted to females; (ii) has Y chromosome, is attracted to males; (iii) does not have Y chromosome, is attracted to males; (iv) does not have Y chromosome, is attracted to females. We call two of these states heterosexual and two of them homosexual. (This ignores the many individuals whose sexual preferences are not so exclusive or rigid).</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">A recent twin study confirms that sexual orientation is moderately heritable – that is, that variation in genes contributes to variation in this trait. These effects are detected by looking at pairs of twins and determining how often, when one of them is homosexual, the other one is too. This rate is much higher (30-50%) in <a href="http://en.wikipedia.org/wiki/Monozygotic#Monozygotic_.28.22identical.22.29_twins">monozygotic</a>, or identical, twins (who share all of their DNA sequence), than in dizygotic, or fraternal, twins (who share only half of their DNA), where the rate is 10-20%. If we assume that the environments of pairs of mono- or dizygotic twins are equally similar, then we can infer that the increased similarity in sexual orientation in pairs of monozygotic twins is due to their increased genetic similarity. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">These data are not yet published (or peer reviewed) but were presented by Dr. Michael Bailey at the recent American Association for the Advancement of Science meeting (Feb 12<sup>th</sup> 2014) and <a href="http://www.theguardian.com/science/2014/feb/14/genes-influence-male-sexual-orientation-study">widely reported on</a>. They confirm and extend findings from multiple previous twin studies across several different countries, which have all found fairly similar results (<a href="http://www.wiringthebrain.com/2010/05/sexual-orientation-in-genes.html">see here</a> for more details). Overall, the conclusion that sexual orientation is partly heritable was already firmly made.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The reaction to news of this recent study reveals a deep disquiet with the idea that homosexuality may arise due to genetic differences. First, there are those who <a href="http://www.theguardian.com/commentisfree/2014/feb/15/gay-gene-dangers-research-homophobia">scoff at the idea </a>that such a complex behaviour could be determined by what may be only a small number of genetic differences – perhaps only one. As I <a href="http://www.wiringthebrain.com/2014/02/reductionism-determinism-straw-man-ism.html">recently discussed</a>, this view is based on a fundamental misunderstanding of what genetic findings really mean. Finding that a trait (a <i style="mso-bidi-font-style: normal;">difference</i> in some system) can be affected by a single genetic difference does not mean a single gene is responsible for crafting the entire system – it simply means that the system does not work normally in the absence of that gene. (Just as a car does not work well without its steering wheel). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Others have expressed a variety of personal and political reactions to these findings, ranging from welcoming further evidence of a biological basis for sexual orientation to worry that it will be used to label homosexuality a genetic disorder and even to enable selective abortion based on genetic prediction. The latter possibility may be made more technically feasible by the other aspect of the recently reported study, which was the claim that they have mapped genetic variants affecting sexual orientation to two specific regions of the <a href="http://en.wikipedia.org/wiki/Genome">genome</a>. (This doesn’t mean they have identified specific genetic variants but may be a step towards doing so). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Let’s explore what the data in this case really show and really mean. A variety of conclusions can be drawn from this and previous studies:</span></div><div class="MsoNormal"><br /></div><div class="MsoListParagraphCxSpFirst" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">1.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">Differences in sexual orientation are partly attributable to genetic differences.</span></div><div class="MsoListParagraphCxSpMiddle" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">2.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">Sexual orientation in males and females is controlled by distinct sets of genes. (Dizygotic twins of opposite sex show no increased similarity in sexual orientation compared to unrelated people – if a female twin is gay, there is no increased likelihood that her twin brother will be too, and vice versa). </span></div><div class="MsoListParagraphCxSpMiddle" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">3.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">Male sexual orientation is rather more strongly heritable than female. </span></div><div class="MsoListParagraphCxSpMiddle" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">4.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">The shared family environment has no effect on male sexual orientation but may have a small effect on female sexual orientation. </span></div><div class="MsoListParagraphCxSpLast" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">5.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">There must also be non-genetic factors influencing this trait, as monozygotic twins are still often discordant (more often than concordant, in fact).</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The fact that sexual orientation in males and females is influenced by distinct sets of genetic variants is interesting and leads to a fundamental insight: heterosexuality is not a single default state. It emerges from distinct biological processes that actively match the brain circuitry of (i) males or (ii) females to their chromosomal and <a href="http://en.wikipedia.org/wiki/Sexual_differentiation">gonadal sex</a> so that most individuals who carry a Y chromosome are attracted to females and most people who do not are attracted to males. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://sites.sinauer.com/levay4e/webtopic05.04.html" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://sites.sinauer.com/levay4e/webtopic05.04.html" border="0" src="http://1.bp.blogspot.com/-gnS-v5McD8M/UzAOvFojVUI/AAAAAAAAAj0/TruJLsZNMaE/s3200/brain+testosterone.jpg" height="270" width="320" /></a><span lang="EN-GB">What is being regulated, biologically, is not sexual orientation (whether you are attracted to people of the same or opposite sex), but sexual preference (whether you are attracted to males or females). Given how complex the processes of <a href="http://www.wiringthebrain.com/2010/04/wired-for-sex.html">sexual differentiation of the brain</a> are (involving the actions of many different genes), it is not surprising that they can sometimes be impaired due to variation in those genes, leading to a failure to match sexual preference to chromosomal sex. Indeed, we know of many specific mutations that can lead to exactly such effects in other mammals – it would be surprising if similar events did not occur in humans. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">These studies are consistent with the idea that sexual preference is a biological trait – an innate characteristic of an individual, not strongly affected by experience or family upbringing. Not a choice, in other words. We didn’t need genetics to tell us that – personal experience does just fine for most people. But this kind of evidence becomes important when some places in the world (<a href="http://news.sciencemag.org/africa/2014/02/science-misused-justify-ugandan-antigay-law">like Uganda</a>, recently) appeal to science to claim (wrongly) that there is evidence that homosexuality is an active choice and use that claim directly to justify criminalisation of homosexual behaviour. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Importantly, the fact that sexual orientation is only <i style="mso-bidi-font-style: normal;">partly</i> heritable does not at all undermine the conclusion that it is a completely biological trait. Just because monozygotic twins are not always concordant for sexual orientation does not mean the trait is not completely innate. Typically, geneticists use the term “non-shared environmental variance” to refer to factors that influence a trait outside of shared genes or shared family environment. The non-shared environment term encompasses those effects that explain why monozygotic twins are actually less than identical for many traits (reflecting additional factors that contribute to variance in the trait across the population generally). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://scousebunintheoven.blogspot.ie/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://scousebunintheoven.blogspot.ie/" border="0" src="http://4.bp.blogspot.com/-mykE9-OtOIU/UzAPCn3-iMI/AAAAAAAAAj8/wFuvBfcETq8/s3200/buns+in+the+oven.jpg" height="240" width="320" /></a><span lang="EN-GB">The terminology is rather unfortunate because “environmental” does not have its normal colloquial meaning in this context. It does not necessarily mean that some experience that an individual has influences their phenotype. Firstly, it encompasses measurement error (just the difficulty in accurately measuring the trait, which is particularly important for behavioural traits). Secondly, it includes environmental effects prior to birth (<i>in utero</i>), which may be especially important for brain development. And finally, it also includes <a href="http://www.wiringthebrain.com/2009/06/nature-nurture-and-noise.html">chance or noise</a> – in this case, intrinsic developmental variation that can have dramatic effects on the end-state or outcome of brain development. This process is incredibly complex and noisy, in engineering terms, and the outcome is, like baking a cake, never the same twice. By the time they are born (when the buns come out of the oven), the brains of monozygotic twins are already highly unique. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Genetic differences may thus change the <i style="mso-bidi-font-style: normal;">probability</i> of an outcome over many instances, without <i style="mso-bidi-font-style: normal;">determining</i> the specific outcome in any individual.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">A useful analogy is to <a href="http://en.wikipedia.org/wiki/Handedness">handedness</a>. Handedness is only <a href="http://www.ncbi.nlm.nih.gov/pubmed/18824185?dopt=Abstract">moderately heritable</a> but is effectively completely innate or intrinsic to the individual. This is true even though the preference for using one hand over the other emerges only over time. The harsh experiences of many in the past who were forced (sometimes with deeply cruel and painful methods) to write with their right hands because left-handedness was seen as aberrant – even sinful – attest to the fact that the innate preference cannot readily be overridden. All the evidence suggests this is also the case for sexual preference.</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.nytimes.com/2011/03/08/health/views/08klass.html?_r=0" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.nytimes.com/2011/03/08/health/views/08klass.html?_r=0 " border="0" src="http://2.bp.blogspot.com/-sp20k9HS14g/UzAPZXAG6lI/AAAAAAAAAkE/ZPU4ElqYQlc/s3200/left-handed+presidents.jpg" height="238" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">What about concerns that these findings could be used as justification for labelling homosexuality a disorder? These are probably somewhat justified – no doubt some people will use it like that. And that places a responsibility on geneticists to explain that just because something is caused by genetic variants – i.e., mutations – does not mean it necessarily should be considered a disorder. We don’t consider red hair a disorder, or blue eyes, or pale skin, or – any longer – left-handedness. All of those are caused by mutations.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The word mutation is rather loaded, but in truth we are all mutants. Each of us carries hundreds of thousands of genetic variants, and <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=22344438">hundreds of those</a> are rare, serious mutations that affect the function of some protein. Many of those cause some kind of difference to our phenotype (the outward expression of our genotype). But a difference is only considered a disorder if it negatively impacts on someone’s life. And homosexuality is only a disorder if society makes it one.</span></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2014/03/gay-genes-yeah-but-no-well-kind-of-but.htmlnoreply@blogger.com (Kevin Mitchell)17tag:blogger.com,1999:blog-6146376483374589779.post-3690235136591438277Sun, 23 Feb 2014 12:40:00 +00002014-02-23T04:40:59.808-08:00geneticsheritabilityintelligencemutationsreductionismsexual orientationReductionism! Determinism! Straw-man-ism!<div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraph, li.MsoListParagraph, div.MsoListParagraph {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraphCxSpFirst, li.MsoListParagraphCxSpFirst, div.MsoListParagraphCxSpFirst {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraphCxSpMiddle, li.MsoListParagraphCxSpMiddle, div.MsoListParagraphCxSpMiddle {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraphCxSpLast, li.MsoListParagraphCxSpLast, div.MsoListParagraphCxSpLast {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} /* List Definitions */ @list l0 {mso-list-id:486434569; mso-list-type:hybrid; mso-list-template-ids:970344292 67698703 67698713 67698715 67698703 67698713 67698715 67698703 67698713 67698715;} @list l0:level1 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level2 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level3 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level4 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level5 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level6 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level7 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level8 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level9 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} ol {margin-bottom:0in;} ul {margin-bottom:0in;} --></style> <br /><div class="MsoNormal"><span lang="EN-GB"></span><span lang="EN-GB"></span><span lang="EN-GB">“Reductionism!” is a charge often flung at geneticists, from accusers in the popular press and also, not infrequently, from many fellow scientists. What is it that leads so many people to so fundamentally misunderstand what genetics is about? </span> </div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Whenever someone presents results showing that variation in such and such a trait is partly influenced by genetic variation, or even showing more specifically that mutations in a particular gene can predispose to a particular outcome, someone is sure to shout: “Reductionism! Single genes can’t cause complex traits – it’s patent nonsense to say that they can! Biological organisms are complex systems interacting in complex ways in an ever-changing environment – particular behaviours can’t be simply determined by genes”.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://thesciencedog.wordpress.com/2013/12/28/beware-the-straw-man/"><img alt="http://thesciencedog.wordpress.com/2013/12/28/beware-the-straw-man/" border="0" src="http://1.bp.blogspot.com/-Xv7I8W21XaM/UwnpUTcgYuI/AAAAAAAAAjA/pqrEfMLwjoI/s1600/straw+man.jpg" height="154" width="320" /></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Of course they are right, but they’re also arguing against something no one is claiming. A couple recent examples illustrate this phenomenon. One is the reaction to <a href="http://www.theguardian.com/science/2014/feb/14/genes-influence-male-sexual-orientation-study">coverage</a> of a presentation at the American Association for the Advancement of Science meeting by Dr. Michael Bailey, which described results of a very large twin study, confirming that sexual orientation has a strong genetic component (explaining 30-40% of the variance in this trait). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Nick Cohen, <a href="http://www.theguardian.com/commentisfree/2014/feb/15/gay-gene-dangers-research-homophobia">writing</a> in The Observer, quoted geneticist Steve Jones’ reaction to the coverage of this story: </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">“The idea that they could find a reductionist explanation for a phenomenon as complicated as human sexuality was, well, optimistic. All you could say was genetic inheritance probably influenced it. But then you could say the same about anything.”</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Cohen goes on to say:</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">“Suppose researchers claim to identify gay genes. Their discovery would be pseudo-science. A Gordian knot of environmental, cultural and hormonal influences would be as important in determining sexual preference.”</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">“To put it another way – if you go along with crude reductionism, you can expect to find yourself at the mercy of crude reductionists.”</span><span lang="EN-GB"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In fact, the scientists presenting these findings were quite careful to spell out that their findings do not show that sexual orientation is completely determined by genes in general or any specific genes in particular. They simply show that genetic variation contributes to variation in this trait and that certain locations in the genome may contain some of the genetic variants responsible. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There have been similar reactions to the <a href="http://www.theguardian.com/education/2014/feb/18/psychologist-robert-plomin-says-genes-crucial-education">discussion</a> of the effects of genetic variation on intelligence and educational achievement. Again, the authors of these studies are circumspect about the impact of genetic effects, highlighting the important role of the environment, and emphasising the complexity of the genetic effects. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The main problem, it seems to me, is a fundamental misunderstanding of what genetics as a science studies and how it relates to the function of complex systems. The following statements are not contradictory:</span></div><div class="MsoNormal"><br /></div><div class="MsoListParagraphCxSpFirst" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">1.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">The function of a complex system emerges from the complex and dynamic interactions between all of the components of the system, in a context- and experience-dependent manner.</span></div><div class="MsoListParagraphCxSpLast" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">2.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">Variation in single components of the system (or in multiple components) can affect how it functions. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Geneticists investigate the second question. Showing that variation in Gene X affects the behaviour or outcome of a system is not the same as saying that Gene X fully determines that behaviour or fully accounts for the entire system. Gene X is just a piece of DNA sitting in a cell somewhere – it doesn’t do anything by itself. But a <i style="mso-bidi-font-style: normal;">difference</i> in Gene X can account for a <i style="mso-bidi-font-style: normal;">difference</i> in how the system works. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There’s nothing reductionist about that, except from a methodological point of view, in that scientists often focus on individual components of complex systems, one at a time, in order to get a handle on that complexity and figure out how the whole system works. That has been an extraordinarily successful approach, but does not mean that scientists employing methodological reductionism also ascribe to <a href="http://en.wikipedia.org/wiki/Reductionism">philosophical reductionism</a> – the idea that the system really can be explained simply from the properties of its lower-level components – that it is no more than the sum of its parts, or that its function can be said to be caused by any one part.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.visualphotos.com/image/2x6178912/mans_hands_holding_steering_wheel" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.visualphotos.com/image/2x6178912/mans_hands_holding_steering_wheel" border="0" src="http://3.bp.blogspot.com/-54Zz5sncMpQ/UwnoqEif8iI/AAAAAAAAAi0/oK1PPWWtGyA/s1600/steering+wheel-2.jpg" height="198" width="200" /><span id="goog_1430439040"></span></a><span id="goog_1430439041"></span><span lang="EN-GB">Consider a car – the function of this wonderful piece of machinery depends on the integrity of all the components and emerges from their interactions. To say that any one component is somehow responsible for the function of the whole system is nonsense. If you just have a steering wheel, you’re not going to get very far. But it’s also true that if you <i style="mso-bidi-font-style: normal;">don’t</i> have a steering wheel, you’re going to have difficulties driving anywhere. A change to one component can drastically affect how even the most complex system functions. </span></div><div class="separator" style="clear: both; text-align: center;"></div><br /><span lang="EN-GB"> </span><span lang="EN-GB">Genetics as an experimental approach studies how a system varies or fails, when individual components are disrupted and uses that information to infer which components are involved in which processes. By contrast, biochemistry or systems biology study how the components of a system are put together and how those interactions mediate its function. These are two complementary experimental approaches to understanding complex systems. (For a very funny analogy along these lines, see <a href="http://bio.research.ucsc.edu/people/kellogg/contents/Demise%20of%20Bill.html">here</a>).</span> <div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">As well as inducing mutations in model organisms to learn how various biological processes work, geneticists also study how naturally occurring genetic variation in a population affects various traits. Again, showing that <i style="mso-bidi-font-style: normal;">differences</i>in genes contribute to <i style="mso-bidi-font-style: normal;">differences</i> in traits is not the same as claiming those genes alone produce or determine everything about the system in question. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://3.bp.blogspot.com/-ZMwgsqn7CuA/UwnqFa574hI/AAAAAAAAAjI/ySnYNmtzSc4/s1600/genes+to+proteins.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://3.bp.blogspot.com/-ZMwgsqn7CuA/UwnqFa574hI/AAAAAAAAAjI/ySnYNmtzSc4/s1600/genes+to+proteins.jpg" height="266" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">Part of the confusion may arise from the two different meanings of the word gene – one based on heredity and the other on molecular biology. In the molecular biology sense, a gene codes for a protein, which carries out some function as a component of some biochemical or cellular system. This is a <i style="mso-bidi-font-style: normal;">productive</i> definition of the gene in relation to the system. By contrast, a gene in the heredity sense really means a variant or mutation in the molecular-biology-gene – something that alters its function and thus alters the system. This is a <i style="mso-bidi-font-style: normal;">disruptive</i> definition of a gene. Such variants can be passed on and contribute to variation in some trait in the population.</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://4.bp.blogspot.com/-99XEsNxobjg/UwnqTssXyaI/AAAAAAAAAjQ/8T-tFHudvCQ/s1600/pencil+erasing+DNA.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-99XEsNxobjg/UwnqTssXyaI/AAAAAAAAAjQ/8T-tFHudvCQ/s1600/pencil+erasing+DNA.jpg" height="196" width="200" /></a></div><div class="MsoNormal"><span lang="EN-GB"></span><span lang="EN-GB">The relationship between a gene (as a piece of DNA coding for a protein) and its function in a biochemical system is thus very different from the relationship between a gene (as a unit of heredity – i.e., a genetic variant) and its effects on some phenotype. For one thing, the effects of a genetic variant can be extremely indirect, cascading across levels from the molecular and biochemical to cellular, physiological and sometimes behavioural. Trying to understand how the phenotypes caused by disrupting a gene relate to the molecular function of the normal gene product is the main enterprise of experimental genetics.</span> </div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Of course, many geneticists contribute to this confusion (often aided and abetted by journalists and headline writers) by using the egregious “<a href="http://www.wiringthebrain.com/2011/11/what-is-gene-for.html">gene for</a>” construct. So, we end up talking about “genes for” schizophrenia or “genes for” intelligence or other traits or conditions – it sounds like these phrases are referring to the productive molecular biology sense of a gene, but really they are using the disruptive heredity sense. What those phrases really refer to is mutations that alter how genes work and that thereby contribute to variation in a particular trait or the likelihood of developing some condition, in the context of the incredibly complex biological system that is a human being, which develops over many years in varying environments. All those qualifiers don’t make for great headlines, I’ll admit, but that’s what the shorthand “gene for” construction really means. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So, claims of genetic influence on various traits are really much more modest than many people seem to think. All they say is that the function of the system in question can vary due to variation in one or more of its components. Hardly the grand threat to civilisation which some people perceive. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">While I am at it, here are some other common and equally misplaced arguments against genetic findings: </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">“I don’t want Trait X to be genetic or innate, so I will simply refuse to believe those data and counter by playing my Reductionist! card”. Political agendas don’t trump scientific facts, thankfully, but this is still a very popular move. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">“If genes underlying Trait X are discovered, people will misuse this knowledge”. This may well be true, but it does not speak to the underlying facts of the matter of whether the trait is really influenced by said genes. (More on this in a later post).</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">“The effects of genetic variation in Gene X are only probabilistic – not everyone with that mutation develops Condition X – how can you therefore <a href="http://www.wiringthebrain.com/2014/01/on-genetic-causality-forwards-and.html">say it is causal</a>?” This is akin to saying that because not everyone who smokes gets lung cancer, you can’t really say that smoking causes lung cancer. (Which is true, if you want to be pedantic about the word “causes”, but we can certainly say it causes a much higher <i style="mso-bidi-font-style: normal;">probability</i> of developing lung cancer. That is a valid, informative and useful statement and we can make analogous statements about the effects of mutations). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">A related one: “The effects of variation in Gene X are only apparent at the statistical level”. Well, the effect of the Y chromosome on height is also only apparent at the statistical level (by comparing the average height of men versus women) but that doesn’t mean it’s not real or useful information. It does mean that this kind of information can’t be reliably applied to make predictions about individuals, which is something some geneticists claim they can do, so this criticism hits the mark in those cases.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">“Geneticists have yet to find any specific genes affecting Trait X, therefore it is not really genetic”. This one really gets my goat, especially because people are often referring to negative results from <a href="http://en.wikipedia.org/wiki/Genome-wide_association_study">genome-wide association studies</a> (GWAS) or the failure of such studies to explain all the heritability of a trait or disorder and claiming that this implies that it is not really heritable after all. As GWAS only look at one kind of genetic variation (common genetic variants) the only thing such negative results imply is that GWAS may be looking in the wrong place and that heritability is likely to also involve many rare genetic variants. <span style="mso-spacerun: yes;">&nbsp;</span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">I am not suggesting that geneticists never overstep the mark and claim more than they should on the basis of specific findings – this field is no more immune from hype than any other – some might argue it is more susceptible, in fact. That is all the more reason to reserve valid arguments against over-extrapolation of genetic results for when they are needed, rather than levelling the blanket, straw-man charge of reductionism! at the field as a whole.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2014/02/reductionism-determinism-straw-man-ism.htmlnoreply@blogger.com (Kevin Mitchell)13tag:blogger.com,1999:blog-6146376483374589779.post-77389752621454475Tue, 07 Jan 2014 18:22:00 +00002014-01-07T10:22:23.357-08:00autismcausalityCNVsgeneticsmutationsneurodevelopmental disorderpredictionschizophreniascreeningOn genetic causality: forwards and backwards<div dir="ltr" style="text-align: left;" trbidi="on"><br /><div style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em; text-align: right;"><img alt="http://www.cftr.info/about-cf/role-of-ctfr-in-cf/cftr-mutations/the-correlation-between-cftr-mutations-and-disease-severity/modifier-genes/ " border="0" src="http://1.bp.blogspot.com/-WNgUkdXxtaE/Usw5MMMuEnI/AAAAAAAAAhM/E22ioCBQUio/s1600/CFTR+modifiers.jpg" height="241" width="320" /></div><br /><br /><br /> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> <br /><div class="MsoNormal"><span lang="EN-GB">Genetics is getting more complicated. Previously clear and strong links between particular mutations and particular diseases are becoming muddied and weaker with increasing knowledge. Such mutations were usually initially identified in families with a heavy burden of illness, where the mutation segregated clearly with illness. But with our increasing ability to sequence large numbers of people, we are now seeing that many such mutations have a much more variable presentation. </span> </div><div class="MsoNormal"><br /></div><span id="goog_1720638727"></span><a href="https://www.blogger.com/"></a><span id="goog_1720638728"></span><div class="MsoNormal"><span lang="EN-GB">Even classically “<a href="http://en.wikipedia.org/wiki/Mendelian_inheritance">Mendelian</a>” mutations, such as those causing <a href="http://en.wikipedia.org/wiki/Cystic_fibrosis">cystic fibrosis</a> and <a href="http://en.wikipedia.org/wiki/Huntington%E2%80%99s_disease">Huntington’s disease</a>, are subject to modifying effects in the genetic background. The same mutation in one person may not cause the same symptoms or disease progression in another. And for more complex “disorders”, such as autism, epilepsy or schizophrenia, these effects are far more endemic. Even in cases where a primary mutation is identifiable, there may often be additional genetic factors that strongly influence the phenotype (not to mention <a href="http://www.wiringthebrain.com/2009/06/nature-nurture-and-noise.html">intrinsic developmental variation</a>, environmental factors and personal experiences, which may all also have a very large influence). Many such mutations can often be found in individuals without any clinical diagnosis. And in many cases, a disease may emerge due to <a href="http://www.wiringthebrain.com/2013/07/no-gene-is-island.html">non-additive interactions</a> between multiple mutations, none of which can be said to be primary.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Given these complexities (even for Mendelian disorders), several commentators, including Anne Buchanan and Ken Weiss, <a href="http://ecodevoevo.blogspot.ie/2013/11/when-causal-disease-alleles-dont-cause.html">here</a>, and Gholson Lyon, <a href="http://biorxiv.org/content/biorxiv/early/2013/11/18/000687.full.pdf">here</a>, have recently questioned the validity of the whole idea of making definitive, categorical genetic diagnoses based on single mutations.<span style="mso-spacerun: yes;"> Both pieces make excellent and valid points.&nbsp; </span></span></div><div class="MsoNormal"><span lang="EN-GB"><br /></span></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.strata-gee.com/2013/06/14/dont-throw-the-baby-out-with-the-bathwater/" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.strata-gee.com/2013/06/14/dont-throw-the-baby-out-with-the-bathwater/" border="0" src="http://4.bp.blogspot.com/-lQ7dgpXLbWA/Usw58krxNnI/AAAAAAAAAhU/8hBieNkqF3A/s1600/Baby,+bathwater.jpg" height="235" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB"></span><span lang="EN-GB">Buchanan and Weiss have argued, convincingly, that the highly variable effects of many specific mutations make them almost useless for prediction of disease based on genotype. While I agree completely about the inherent complexity of relating single genotypes to phenotypes (as discussed here), I think it is important not to throw the baby out with the bathwater. In particular, a clear distinction should be drawn between <i>explanation</i> and <i>prediction</i>, as the probability relationships are entirely different in these two directions. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This can be illustrated with a couple of examples of specific mutations that increase risk of neurodevelopmental disorders. Most mutations associated with these conditions show “<a href="http://en.wikipedia.org/wiki/Incomplete_penetrance">incomplete penetrance</a>” – that simply means that not everyone who carries the mutation develops the disease (or, more accurately, not all carriers are given the diagnosis). For example, about 30% of carriers of a chromosomal <a href="http://en.wikipedia.org/wiki/22q11.2_deletion_syndrome">deletion at 22q11.2</a> develop psychosis and would meet criteria for a diagnosis of schizophrenia. This is a hugely increased risk over the baseline population rate of ~1%, but obviously still far from a majority of carriers. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">[As an aside, it is important to note that the value determined for the penetrance depends entirely on what phenotype we are assessing. If it is whether the individual has been given a diagnosis of schizophrenia, then it is around 30% for 22q11.2 deletions. But if it includes clinically determined intellectual disability, developmental delay or autism, then the <a href="http://www.ncbi.nlm.nih.gov/pubmed/23992924">penetrance approaches 100%</a>. Indeed, a recent study found <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=24352232">general effects on cognition</a> even in clinically “unaffected” carriers of this and many other recurrent chromosomal aberrations only sometimes associated with frank disease]. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">What can we say, based on these numbers? For prediction, we are asking, given the presence of mutation X, what is the likelihood of disease Y? The only thing we can currently base that on is the frequency of disease in carriers of a given mutation. To follow the example above, given the presence of a 22q11.2 deletion, the risk of developing schizophrenia is 30%. Other known mutations associated with neurodevelopmental disorders have differing penetrance – for example, only ~6% of carriers of a <a href="http://en.wikipedia.org/wiki/Neurexin">NRXN1</a> deletion develop schizophrenia and only a third are clinically affected overall (versus nearly 100% of 22q11 deletion carriers). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Those numbers make predictions of the prognosis of individual mutation-carriers pretty fuzzy. With a disease like schizophrenia, this kind of prediction is clinically important as there may be methods to intervene during pre-morbid or prodromal phases of the illness, prior to the onset of frank psychosis and the full clinical syndrome. But current medical interventions in individuals at high risk of developing psychosis <a href="http://www.ncbi.nlm.nih.gov/pubmed/23436256">employ the crude hammer</a> of antipsychotic medication, with all the attendant downsides and potentially serious side-effects – not something to be taken lightly or administered without strong justification.&nbsp; </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">On the other hand, risks of the magnitude referred to above may well represent actionable information in terms of <a href="http://www.wiringthebrain.com/2012/05/gattaca-and-coming-future-of-genetic.html">prenatal screening</a> and reproductive decisions. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://manausa.com/yogi-berra-selling-a-house/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://manausa.com/yogi-berra-selling-a-house/" border="0" src="http://4.bp.blogspot.com/-hGgPjAohnE8/Usw6-A014_I/AAAAAAAAAhg/yaaNc0e_yLc/s1600/Yogi+Berra.jpg" height="320" width="223" /></a></div><div class="MsoNormal"><span lang="EN-GB">Nevertheless, predictions based on genetic information will remain drastically underpowered until we reach a point where the risk associated with an individual’s entire genome-type, and not just with a single mutation, can be assessed. Making predictions is hard, especially about the future (Niels Bohr or Yogi Berra, depending on who you ask).</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">But what about going in the opposite direction? This is really a very different situation. If we find an individual with disease Y and with mutation X, can we infer that the mutation is the cause of the disease? Here, we start with two givens (two rare events) and want to infer the likely relationship between them (based on their known contingency). So, if we have a patient with schizophrenia and a test shows they carry a 22q11.2 deletion, how strongly can we infer that that deletion is the primary cause of their illness? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">I suppose there is a fancier statistical way to do this, but naïvely, we can say that if that person did <i>not</i> have that mutation, their likelihood of having schizophrenia would only have been ~1% (given no other relevant information). So, I think it right to say, intuitively, that it is 30-fold more likely that their disease was caused by the 22q11 deletion than by some other, unknown factor.</span><span lang="EN-GB"> </span><span lang="EN-GB">We can put more definite numbers on this as follows:</span> </div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Likelihood of causality = (P(Disease|Mutation) – P(Disease|No information)) /P(Disease|Mutation)</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The P(A|B) notation means the probability of A, given B, which we are going to compare to the <a href="http://en.wikipedia.org/wiki/Prior_probability">prior probability</a> of A, given no knowledge of B. Because we take the presence of the mutation as a given, these calculations should be independent of the frequency of the mutation (I think). For 22q11 deletions, this odds ratio comes to 29/30, which corresponds to about a 96.7% probability. For NRXN1 deletions, the penetrance is much lower – 6.4% vs 1% baseline – but the inference of causality still comes out to 84.4%. (Another way to word this is, if we take 1000 individuals with NRXN1 deletions, we would expect 64 to have schizophrenia. But 10 of those would be expected anyway, so we can say the increased burden in this group, which we can equate to the likelihood of causality of the NRXN1 mutation in any individual is 54/64 = 84.4%). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">I feel like I may have just committed some egregious statistical sin with the way that last statement is worded, but it’s not that important. Those calculations are very naïve (and not something any clinical geneticist actually carries out), but I think they capture the general intuition – if the known penetrance of a mutation for a particular disease is higher, then the inference of causality is stronger when you find someone with both the disease and the mutation. They also illustrate a surprising result: even in cases where predictive power is quite low (only about 6%), <i>post hoc</i>explanatory power may still be quite high – because now we’re given the presence of disease, an otherwise rare event. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">[This is somewhat analogous to interpreting medical tests in a <a href="http://en.wikipedia.org/wiki/Bayesian_probability">Bayesian</a> framework, by comparing the false positive rate to the underlying prevalence of the condition being screened for (the prior probability) – see <a href="http://crackingtheenigma.blogspot.ie/2012/09/a-genetic-test-for-autism.html">here</a> for a great example of this counter-intuitive effect, in the context of autism].</span></div><div class="MsoNormal"><span lang="EN-GB"><br /></span></div><div class="MsoNormal"><span lang="EN-GB">Now, when we use a word like “cause” we are wading into some treacherous philosophical waters. When I use it here, I do not mean that the presence of the mutation is a <i style="mso-bidi-font-style: normal;">sufficient</i>cause of the illness, nor is it a complete explanation of the person’s phenotype. But calculations of the type shown above give a value to the strength of the inference that a particular mutation was a <i style="mso-bidi-font-style: normal;">necessary</i> condition for the emergence of illness in that individual. They allow us to assign a probability to the idea that, of all the factors and events that led to illness in this person, the presence of the mutation was a <a href="http://philsci-archive.pitt.edu/3833/1/WatersCausesMD_Preprint.pdf"><i style="mso-bidi-font-style: normal;">difference-maker</i></a>. It was the main culprit, even if there were multiple accomplices.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This is not causality in a reductive sense (where a single cause fully explains the entire phenotype), but in a <a href="http://plato.stanford.edu/entries/causation-counterfactual/">counterfactual</a> sense (where a single difference explains a difference in the phenotype – in this case, developing disease versus not developing it). It says, if cause X had not been the case, then phenotype Y would not have arisen. For cases like cystic fibrosis and Huntington’s disease, this inference is rock solid – these disorders do not arise without mutations in the <a href="http://ghr.nlm.nih.gov/gene/CFTR">CFTR gene</a> or the <a href="http://ghr.nlm.nih.gov/condition/huntington-disease">Htt gene</a> (even if the disease symptoms and progression can be affected by modifying mutations in other genes). For examples like the mutations listed above that lead to common neurodevelopmental disorders, where there are multiple causes across the population, the best we can do is assign a probability of causal involvement for any particular potentially pathogenic mutation discovered, based on rates of illness across many carriers of that mutation, compared to the baseline rate. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.senescence.info/aging_models.html" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="http://www.senescence.info/aging_models.html" border="0" src="http://1.bp.blogspot.com/-vQipOQzCeRU/UsxAIS9jNwI/AAAAAAAAAh4/4RzVOp3foEI/s1600/model+organisms.jpg" /></a></div><div class="MsoNormal"><span lang="EN-GB">At least, that’s usually the best we can do for humans – we can do a lot better in animal models that are amenable to experimental manipulation. When worm or fly or mouse geneticists map and identify a mutation that they think is causing a particular phenotype, they can do two different experiments to test that hypothesis. First, they can introduce the same mutation into a different animal and see if it reproduces the phenotype. And second, they can repair the mutation in the initial line of animals and see if it rescues the phenotype. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Obviously we can’t do those kinds of things in humans, but we can approach those kinds of experimental tests of causality in two ways. First, we can introduce the putatively causal mutation into an animal and see if it recapitulates known aspects of the disease phenotype (<a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=22078115">in an animal sense</a>). This is very indirect and suffers from many caveats (especially in knowing which phenotypes to look for and in interpreting negative results) but a positive result in some validated assay does give some confidence that the suspect mutation is having an important and relevant effect. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The second approach relies on two fairly new technologies – the first is the development of induced pluripotent stem cells (<a href="http://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell">iPS cells</a>) from human patients. These can be differentiated in a dish into many different cell types and tissues, which can be tested for cellular-level phenotypes relevant to the function of the damaged gene. This system is obviously highly simplified and far from ideal, especially for disorders that manifest at a physiological or even psychological level, but even in those cases, they must arise initially from changes in the way cells function and these may be definable if we can assay the right cell types in the right ways.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Testing causality of a particular mutation for any such phenotype in a patient’s cells can now be achieved using an even newer technology: the <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=crispr+craze">CRISPR method</a> of genome editing. This uses an RNA guide molecule to direct an enzyme to cut the DNA in the genome at a specific position (with astonishingly, game-changingly high efficiency). If a non-mutant template is supplied, this break will be repaired in such a way as to change the sequence of DNA in that region, providing the means to revert a mutation to the “wild-type” version. Then one can determine whether it was really that single mutation that led to the cellular phenotype or, alternatively, if it was not involved at all or only one of many factors contributing. (Exciting proof of principle of this approach was recently provided in a <a href="http://www.ncbi.nlm.nih.gov/pubmed/24315440">mouse model of cataracts</a> and in cultured intestinal stem cells <a href="http://www.ncbi.nlm.nih.gov/pubmed/24315439">from cystic fibrosis patients</a>). <span style="mso-spacerun: yes;">&nbsp;</span></span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.impawards.com/tv/house_md_ver4.html" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.impawards.com/tv/house_md_ver4.html " border="0" src="http://1.bp.blogspot.com/-Hu7LofEFKKw/Usw7PwjYSYI/AAAAAAAAAho/CIvL2NHDsF4/s1600/House+MD.jpg" height="320" width="216" /></a></div><div class="MsoNormal"><span lang="EN-GB">Now, for most diseases, we don’t currently have good animal models or proxies at the cellular level. But there is an analogous approach to the rescue experiment that can be performed in humans for some conditions – that is to treat with a medication that targets the candidate pathogenic molecular mechanism. If the patient improves, then we can conclude that that mutation was in fact making a major contribution to their illness. This is the “<a href="http://en.wikipedia.org/wiki/House_%28TV_series%29">House, M.D.</a>” method of confirming a diagnosis (it’s never lupus). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Of course, for most mutations, no such specifically tailored medication currently exists. But there are a few exceptions for neurodevelopmental disorders. <a href="http://en.wikipedia.org/wiki/Fragile_X_syndrome">Fragile X syndrome</a> is one – this condition is a common cause of autism, accounting for 2-3% of cases. Research <a href="http://www.ncbi.nlm.nih.gov/pubmed/21090964">over several decades</a> has established the nature of the molecular defect in Fragile X patients and the cellular consequences in how nerve cell synapses work, and is beginning to elucidate the emergent physiological consequences on neural networks and brain systems. This detailed knowledge has led to the identification of candidate cellular components that can be targeted to restore the balance of the biochemical pathway affected by the Fragile X mutation. This approach <a href="http://www.ncbi.nlm.nih.gov/pubmed/21090964">shows great promise</a> in animal models of the disorder and is currently in clinical trials. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB"><a href="http://en.wikipedia.org/wiki/Tuberous_sclerosis">Tuberous sclerosis</a> is another genetic condition also often associated with symptoms of autism. It is caused by mutations in either one of two other genes, which also encode proteins that function in synapses. However, when these genes are mutated the biochemical defect is the opposite of that when the Fragile X gene is mutated. It turns out that if this pathway is either too active or not active enough, the functions of neural synapses are impaired, especially in how they change in response to activity. Either situation can lead to autism. In mice, crossing Fragile X mutants with tuberous sclerosis mutants actually restores the balance of this pathway and the resultant <a href="http://www.ncbi.nlm.nih.gov/pubmed/22113615">double mutants are much more normal</a> than either single mutant alone. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So, if a child comes into a clinic with symptoms of autism, it is important to know if they have mutations in Fragile X or the tuberous sclerosis genes because the medication that may prove beneficial for Fragile X patients would be likely to <a href="http://www.ncbi.nlm.nih.gov/pubmed/22113615">exacerbate symptoms</a> in those with tuberous sclerosis mutations. (And, of course, there are hundreds of other potential causes of autistic symptoms that may also respond differently or not at all). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">But even for cases where no targeted medication exists, the identification of a putatively pathogenic mutation can still inform clinical treatment. Once a large enough database is generated, clinicians will be able to ask how patients with different mutations respond to currently available medications. Perhaps schizophrenic people with 22q11.2 deletions respond better to typical antipsychotics than people with NRXN1 deletions. Or maybe some medications should be avoided in the presence of certain mutations – that is the case for mutations in a sodium channel gene, which are associated with <a href="http://en.wikipedia.org/wiki/Dravet_syndrome">Dravet syndrome</a>, a common form of epilepsy. Patients with these mutations should not be treated with traditional anticonvulsants as this is known to worsen their seizures. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">To avoid semantic arguments, we should just probably not use the term “genetic diagnosis” and replace it with “genetic information”. I agree completely that a genetic diagnosis will often be too categorical and definitive, conferring a label based only on one component of a person’s genetic make-up, which may in turn be only one factor in their disease. But despite these complexities, the identification of major mutations still provides very useful genetic information that will often be relevant to the patient’s prognosis and treatment.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">With thanks to Dan Bradley, John McGrath (@John_J_McGrath), Gholson Lyon (@GholsonLyon), Svetlana Molchanova (@Svetadotfi) and Shane McKee (@shanemuk) for useful and stimulating discussions. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The following articles have some interesting philosophical discussion of causality, especially in relation to genetics:</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Mackie, J.L. (1965) Causes and conditions. American Philosophical Quarterly, vol 2, no. 4. <a href="http://www.jstor.org/discover/10.2307/20009173?uid=3738232&amp;uid=2129&amp;uid=2&amp;uid=70&amp;uid=4&amp;sid=21103215076571">http://www.jstor.org/discover/10.2307/20009173?uid=3738232&amp;uid=2129&amp;uid=2&amp;uid=70&amp;uid=4&amp;sid=21103215076571</a></span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span lang="EN-GB">Meehl (1997) </span><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">Specific Etiology and Other Forms of Strong Influence: Some</span></div><div class="MsoNormal"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">Quantitative Meanings. The Journal of Medicine and Philosophy, 1977, vol. 2, no. 1. <a href="http://jmp.oxfordjournals.org/content/2/1/33.extract">http://jmp.oxfordjournals.org/content/2/1/33.extract</a></span><span lang="EN-GB"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Waters, C.K. (2007) Causes that make a difference. </span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Journal of Philosophy 104 (11):551-579 <a href="http://philsci-archive.pitt.edu/3833/1/WatersCausesMD_Preprint.pdf">http://philsci-archive.pitt.edu/3833/1/WatersCausesMD_Preprint.pdf</a></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span lang="EN-GB">Kendler, K.S. (2012) </span><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;;">The dappled nature of causes of psychiatric illness: replacing the organic–functional/hardware–software dichotomy with empirically based pluralism </span><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Apr;17(4):377-88. <span style="mso-spacerun: yes;">&nbsp;</span><a href="http://www.ncbi.nlm.nih.gov/pubmed/22230881">http://www.ncbi.nlm.nih.gov/pubmed/22230881</a></span></div></div>http://www.wiringthebrain.com/2014/01/on-genetic-causality-forwards-and.htmlnoreply@blogger.com (Kevin Mitchell)5tag:blogger.com,1999:blog-6146376483374589779.post-1079472632462088004Thu, 07 Nov 2013 18:18:00 +00002013-11-12T08:50:07.405-08:00autismcommon variantsGCTAgeneticsGWASpsychiatric geneticsrare variantsschizophreniastatisticsThe dark arts of statistical genomics<div dir="ltr" style="text-align: left;" trbidi="on"><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-520092929 1073786111 9 0 415 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} @font-face {font-family:"Minion Pro"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-alt:Cambria; mso-font-charset:77; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:auto; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} span.highlight {mso-style-name:highlight; mso-style-unhide:no;} p.Default, li.Default, div.Default {mso-style-name:Default; mso-style-unhide:no; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:none; mso-layout-grid-align:none; text-autospace:none; font-size:12.0pt; font-family:"Minion Pro","serif"; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-bidi-font-family:"Minion Pro"; color:black;} span.A3 {mso-style-name:A3; mso-style-priority:99; mso-style-unhide:no; mso-style-parent:""; mso-ansi-font-size:6.5pt; mso-bidi-font-size:6.5pt; font-family:"Minion Pro","serif"; mso-bidi-font-family:"Minion Pro"; color:black;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style></div>--&gt; <div class="MsoNormal"><span lang="EN-GB">“</span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"><i>Whereof one cannot speak, thereof one must be silent</i>” - Wittgenstein</span><span lang="EN-GB"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">That’s a maxim to live by, or certainly to blog by, but I am about to break it. Most of the time I try to write about things I feel I have some understanding of (rightly or wrongly) or at least an informed opinion on. But I am writing this post from a position of ignorance and confusion. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">I want to discuss a fairly esoteric and technical statistical method recently applied in human genetics, which has become quite influential. The results from recent studies using this approach have a direct bearing on an important question – the genetic architecture of complex diseases, such as schizophrenia and autism. And that, in turn, dramatically affects how we conceptualise these disorders. But this discussion will also touch on a much wider social issue in science, which is how highly specialised statistical claims are accepted (or not) by biologists or clinicians, the vast majority of whom are unable to evaluate the methodology. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Speak for yourself, you say! Well, that is exactly what I am doing.</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://myfoodsafetyblog.blogspot.ie/2008/06/animal-pharm-on-cna.html" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://myfoodsafetyblog.blogspot.ie/2008/06/animal-pharm-on-cna.html" border="0" height="215" src="http://3.bp.blogspot.com/-m1fgO7KObqI/UnvPQikIDsI/AAAAAAAAAf0/rNHZaa7OvOY/s320/cattle+breeding.jpg" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">The technique in question is known as </span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"><a href="http://www.ncbi.nlm.nih.gov/pubmed/21167468">Genome-wide Complex Trait Analysis</a> (or <span class="highlight">GCTA</span>). It is based on methods developed in animal breeding, which are designed to measure the “breeding quality” of an animal using genetic markers, without necessarily knowing which markers are really linked to the trait(s) in question. The method simply uses molecular markers across the genome to determine how closely an animal is related to some other animals with desirable traits. Its <a href="http://www.giga.ulg.ac.be/upload/docs/application/pdf/2011-09/goddard_nrg_2009.pdf">application</a> has led to huge improvements in the speed and efficacy of selection for a wide range of traits, such as milk yield in dairy cows.<span style="mso-spacerun: yes;">&nbsp; </span><span style="mso-spacerun: yes;">&nbsp;</span></span><span lang="EN-GB"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">GCTA has recently been applied in human genetics in an innovative way to explore the genetic architecture of various traits or common diseases. The term <a href="http://en.wikipedia.org/wiki/Genetic_architecture">genetic architecture</a> refers to the type and pattern of genetic variation that affects a trait or a disease across a population. For example, some diseases are caused by mutations in a single gene, like <a href="http://en.wikipedia.org/wiki/Cystic_fibrosis">cystic fibrosis</a>. Others are caused by mutations in any of a large number of different genes, like congenital deafness, intellectual disability, <a href="http://en.wikipedia.org/wiki/Retinitis_pigmentosa">retinitis pigmentosa</a> and many others. In these cases, each such mutation is typically very rare – the prevalence of the disease depends on how many genes can be mutated to cause it. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For common disorders, like heart disease, diabetes, autism and schizophrenia, this model of causality by rare, single mutations has been questioned, mainly because such mutations have been hard to find. An <a href="http://en.wikipedia.org/wiki/Common_disease-common_variant">alternative model</a> is that those disorders arise due to the inheritance of many risk variants that are actually common in the population, with the idea that it takes a large number of them to push an individual over a threshold of burden into a disease state. Under this model, we would all carry many such risk variants, but people with disease would carry more of them. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.broadinstitute.org/education/glossary/snp" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.broadinstitute.org/education/glossary/snp " border="0" src="http://4.bp.blogspot.com/-AfN96ZfnE1Q/UnvPfw9sn7I/AAAAAAAAAf8/6DvabvudH3o/s1600/SNP.jpg" /></a></div><div class="MsoNormal"><span lang="EN-GB">That idea can be tested in <a href="http://en.wikipedia.org/wiki/Genome-wide_association_study">genome-wideassociation studies </a>(GWAS). These use molecular methods to look at many, many sites in the genome where the DNA code is variable (it might be an “A” 30% of the time and a “T” 70% of the time). The vast majority of such sites (known as <a href="http://en.wikipedia.org/wiki/Single-nucleotide_polymorphism">single-nucleotide polymorphisms</a> or SNPs) are not expected to be involved in risk for the disease, but, if one of the two possible variants at that position is associated with an increased risk for the disease, then you would expect to see an increased frequency of that variant (say the “A” version) in a cohort of people affected by the disease (cases) versus the frequency in the general population (controls). So, if you look across the whole genome for sites where such frequencies differ between cases and controls you can pick out risk variants (in the example above, you might see that the “A” version is seen in 33% of cases versus 30% of controls). Since the effect of any one risk variant is very small by itself, you need very large samples to detect statistically significant signals of a real (but small) difference in frequency between cases and controls, amidst all the noise. <span style="mso-spacerun: yes;">&nbsp;</span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">GWAS have been quite successful in identifying many variants showing a statistical association with various diseases. Typically, each one has a tiny statistical effect on risk by itself, but the idea is that collectively they increase risk a lot. <i style="mso-bidi-font-style: normal;">But how much is a lot?</i> That is a key question in the field right now. Perhaps the aggregate effects of common risk variants explain all or the majority of variance in the population in who develops the disease. If that is the case then we should invest more efforts into finding more of them and figuring out the mechanisms underlying their effects.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Alternatively, maybe they play only a minor role in susceptibility to such conditions. For example, the genetic background of such variants might modify the risk of disease but only in persons who inherit a rare, and seriously deleterious mutation. This modifying mechanism might explain some of the variance in the population in who does and does not develop that disease, but it would suggest we should focus more attention on finding those rare mutations than on the modifying genetic background.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For most disorders studied so far by GWAS, the amount of variance collectively explained by the currently identified common risk variants is quite small, typically on the order of a few percent of the total variance. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.boostsuite.com/2012/07/24/are-you-picking-your-low-hanging-seo-fruit/" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.boostsuite.com/2012/07/24/are-you-picking-your-low-hanging-seo-fruit/ " border="0" height="233" src="http://2.bp.blogspot.com/--FSBjNv89DA/UnvQez2Rw6I/AAAAAAAAAgU/kRYt0swxk8g/s320/low+hanging+fruit.jpg" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">But that doesn’t really put a limit on how much of an effect all the putative risk variants <i style="mso-bidi-font-style: normal;">could have</i>, because we don’t know how many there are. If there is a huge number of sites where one of the versions increases risk very, very slightly (<a href="http://rstb.royalsocietypublishing.org/content/365/1537/73.full">infinitesimally</a>), then it would require really vast samples to find them all. Is it worth the effort and the expense to try and do that? Or should we be happy with the low-hanging fruit and invest more in finding rare mutations?<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This is where GCTA analyses come in. The idea here is to estimate the total contribution of common risk variants in the population to determining who develops a disease, without necessarily having to identify them all individually first. The basic premise of GCTA analyses is to not worry about picking up the signatures of individual SNPs, but instead to use all the SNPs analysed to simply measure relatedness among people in your study population. Then you can compare that index of (distant) relatedness to an index of phenotypic similarity. For a trait like height, that will be a correlation between two continuous measures. For diseases, however, the phenotypic measure is categorical – you either have been diagnosed with it or you haven’t. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So, for diseases, what you do is take a large cohort of affected cases and a large cohort of unaffected controls and analyse the degree of (distant) genetic relatedness among and between each set. What you are looking for is a signal of greater relatedness among cases than between cases and controls – this is an indication that liability to the disease is: (i) genetic, and (ii) affected by variants that are shared across (very) distant relatives.</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://ngm.nationalgeographic.com/2012/01/twins/miller-text" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://ngm.nationalgeographic.com/2012/01/twins/miller-text" border="0" height="251" src="http://3.bp.blogspot.com/-YKmQRjCg578/UnvPvu_4dmI/AAAAAAAAAgE/JTO2vsot70E/s320/national+geographic+twins.jpg" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">The logic here is an inversion of the normal process for estimating <a href="http://en.wikipedia.org/wiki/Heritability">heritability</a>, where you take people with a certain degree of genetic relatedness (say monozygotic or dizygotic twins, siblings, parents, etc.) and analyse how phenotypically similar they are (what proportion of them have the disease, given a certain degree of relatedness to someone with the disease). For common disorders like autism and schizophrenia, the proportion of monozygotic twins who have the disease if their co-twin does is much higher than for dizygotic twins. The difference between these rates can be used to estimate how much genetic differences contribute to the disease (the heritability).</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">With GCTA, you do the opposite – you take people with a certain degree of phenotypic similarity (they either are or are not diagnosed with a disease) and then analyse how genetically similar they are. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">If a disorder were completely caused by rare, recent mutations, which would be highly unlikely to be shared between distant relatives, then cases with the disease should not be any more closely related to each other than controls are. The most dramatic examples of that would be cases where the disease is caused by de novo mutations, which are not even shared with close relatives (as in <a href="http://en.wikipedia.org/wiki/Down_syndrome">Down syndrome</a>). If, on the other hand, the disease is caused by the effects of many common, ancient variants that float through the population, then enrichment for such variants should be heritable, possibly even across distant degrees of relatedness. In that situation, cases will have a more similar SNP profile than controls do, on average.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now, say you do see some such signal of increased average genetic relatedness among cases. What can you do with that finding? This is where the tricky mathematics comes in and where the method becomes opaque to me. The idea is that the precise quantitative value of the increase in average relatedness among cases compared to that among controls can be extrapolated to tell you how much of the heritability of the disorder is attributable to common variants. How this is achieved with such specificity eludes me. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Let’s consider how this has been done for schizophrenia. A <a href="http://www.ncbi.nlm.nih.gov/pubmed/22344220">2012 study</a> by Lee and colleagues analysed multiple cohorts of cases with schizophrenia and controls, from various countries. These had all been genotyped for over 900,000 SNPs in a previous GWAS, which hadn’t been able to identify many individually associated SNPs. </span></div><div class="MsoNormal"><br /></div><div class="Default">Each person’s SNP profile was compared to each other person’s profile (within and between cohorts), generating a huge matrix. The mean genetic similarity was then computed among all pairs of cases and among all pairs of controls. Though these are the actual main results – the raw findings – of the paper, they are remarkably not presented in the paper. Instead, the results section reads, rather curtly: </div><div class="MsoNormal"><br /></div><div class="Default"><span style="font-size: 9.0pt;">Using a linear mixed model (see Online Methods), we estimated the proportion of variance in liability to schizophrenia explained by SNPs (<i>h</i></span><span class="A3"><span style="font-size: 6.5pt;">2</span></span><span style="font-size: 9.0pt;">) in each of these three independent data subsets. … The individual estimates of <i>h</i></span><span style="font-size: 6.5pt;">2 </span><span style="font-size: 9.0pt;">for the ISC and MGS subsets and for other samples from the PGC-SCZ were each greater than the estimate from the total com­bined PGC-SCZ sample of <i>h</i></span><span style="font-size: 6.5pt;">2 </span><span style="font-size: 9.0pt;">= 23% (s.e. = 1%)</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So, some data we are not shown (the crucial data) are fed into a model and out pops a number and a strongly worded conclusion: 23% of the variance in the trait is tagged by common SNPs, mostly functionally attributable to common variants*. <span style="color: red;">*[See important clarification in the comments below - it is really the entire genetic matrix that is fed into the models, not just the mean relatedness as I suggested here. Conceptually, the effect is still driven by the degree of increased genetic similarity amongst cases, however].</span> This number has already become widely cited in the field and used as justification for continued investment in GWAS to find more and more of these supposed common variants of ever-decreasing effect. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now I’m not saying that that number is not accurate but I think we are right to ask whether it should simply be taken as an established fact. This is especially so given the history of how similar claims have been uncritically accepted in this field.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In the early 1990s, a <a href="http://www.ncbi.nlm.nih.gov/pubmed/2184091">couple</a> of <a href="http://www.ncbi.nlm.nih.gov/pubmed/2301392">papers</a> came out that supposedly proved, or at least were read as proving, that schizophrenia could not be caused by single mutations. Everyone knew it was obviously not always caused by mutations in one specific gene, in the way that cystic fibrosis is. But these papers went further and rejected the model of genetic heterogeneity that is characteristic of things like inherited deafness and retinitis pigmentosa. This was based on a combination of arguments and statistical modelling. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The arguments were that if schizophrenia were caused by single mutations, they should have been found by the extensive linkage analyses that had already been carried out in the field. If there were a handful of such genes, then this criticism would have been valid, but if that number were very large then one would not expect consistent linkage patterns across different families. Indeed, the way these studies were carried out – by combining multiple families – would virtually ensure you would <a href="http://www.wiringthebrain.com/2012/08/why-have-genetic-linkage-studies-of.html">not find anything</a>. The idea that the disease could be caused by mutations in any one of a very large number (perhaps hundreds) of different genes was, however, rejected out of hand as inherently implausible. [See <a href="http://www.wiringthebrain.com/2013/03/the-genetics-of-emergent-phenotypes.html">here</a> for a discussion of why a phenotype like that characterising schizophrenia might actually be a common outcome].</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.schizophrenia.com/research/hereditygen.htm" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.schizophrenia.com/research/hereditygen.htm " border="0" height="246" src="http://1.bp.blogspot.com/-LdtJ5Npot1M/UnvQHxydhWI/AAAAAAAAAgM/LGXOk6P83NQ/s320/SZ+relative+risk.jpg" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">The statistical modelling was based on a set of numbers – the relative risk of disease to various family members of people with schizophrenia. Classic studies found that monozygotic twins of schizophrenia cases had a 48% chance (frequency) of having that diagnosis themselves. For dizygotic twins, the frequency was 17%. Siblings came in about 10%, half-sibs about 6%, first cousins about 2%. These figures compare with the population frequency of ~1%. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The statistical modelling inferred that this pattern of risk, which decreases at a faster than linear pace with respect to the degree of genetic relatedness, was inconsistent with the condition arising due to single mutations. By contrast, these data were shown to be consistent with an <a href="http://medical-dictionary.thefreedictionary.com/oligogenic">oligogenic</a> or <a href="http://medical-dictionary.thefreedictionary.com/polygenic">polygenic</a> architecture in affected individuals. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There was however, a crucial (and rather weird) assumption – that singly causal mutations would all have a <a href="http://en.wikipedia.org/wiki/Dominance_%28genetics%29">dominant mode of inheritance</a>. Under that model, risk would decrease linearly with distance of relatedness, as it would be just one copy of the mutation being inherited. This contrasts with <a href="http://en.wikipedia.org/wiki/Recessive">recessive</a> modes requiring inheritance of two copies of the mutation, where risk to distant relatives drops dramatically. There was also an important assumption of negligible contribution from <a href="http://ghr.nlm.nih.gov/glossary=denovomutation">de novo mutations</a>. As it happens, it is trivial to come up with <a href="http://www.ncbi.nlm.nih.gov/pubmed/20380786">some division of cases</a> into dominant, recessive and de novo modes of inheritance that collectively generate a pattern of relative risks similar to observed. (Examples of all such modes of inheritance have now been identified). Indeed, there is an <a href="http://www.ncbi.nlm.nih.gov/pubmed/5106369">infinite number of ways</a> to set the (many) relevant parameters in order to generate the observed distribution of relative risks. It is impossible to infer backwards what the actual parameters are. Not merely difficult or tricky or complex – impossible.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Despite these limitations, these papers became hugely influential. The conclusion – that schizophrenia <i style="mso-bidi-font-style: normal;">could not</i> be caused by mutations in (many different) single genes – became taken as a proven fact in the field. The corollary – that it must be caused instead by combinations of common variants – was similarly embraced as having been conclusively demonstrated.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This highlights an interesting but also troubling cultural aspect of science – that some claims are based on methodology that many of the people in the field cannot evaluate. This is especially true for highly mathematical methods, which most biologists and psychiatrists are ill equipped to judge. If the authors of such claims are generally respected then many people will be happy to take them at their word. In this case, these papers were highly cited, spreading the message beyond those who actually read the papers in any detail.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In retrospect, these conclusions are fatally undermined not by the mathematics of the models themselves but by the simplistic assumptions on which they are based. With that precedent in mind, let’s return to the GCTA analyses and the strong claims derived from them. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Before considering how the statistical modelling works (I don’t know) and the assumptions underlying it (we’ll discuss these), it’s worth asking what the raw findings actually look like. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">While the numbers are not provided in this paper (not even in the extensive supplemental information), we can look at similar data from a study by the same authors, using cohorts for several other diseases (Crohn’s disease, bipolar disorder and type 1 diabetes).</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.ncbi.nlm.nih.gov/pubmed/21376301"><img alt="http://www.ncbi.nlm.nih.gov/pubmed/21376301 " border="0" height="200" src="http://2.bp.blogspot.com/-CJFTW9q0Uo0/UnvQ1DEthYI/AAAAAAAAAgc/pFtE-7mmuHg/s640/Lee-2011-Table+2.png" width="640" /></a></div><div class="MsoNormal"><span lang="EN-GB"><br /></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Those numbers are a measure of mean genetic similarity (i) among cases, (ii) among controls and (iii) between cases and controls. The important finding is that the mean similarity among cases or among controls is (very, very slightly) greater than between cases and controls. All the conclusions rest on this primary finding. Because the sample sizes are fairly large and especially because all pairwise comparisons are used to derive these figures, this result is highly statistically significant. But what does it mean?</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The authors remove any persons who are third cousins or closer, so we are dealing with very distant degrees of genetic relatedness in our matrix. One problem with looking just at the mean level of similarity between all pairs is it tells us nothing about the pattern of relatedness in that sample. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Is the small increase in mean relatedness driven by an increase in relatedness of just some of the pairs (equivalent to an excess of fourth or fifth cousins) or is it spread across all of them? Is there any evidence of clustering of multiple individuals into subpopulations or clans? Does the similarity represent “<a href="http://en.wikipedia.org/wiki/Identity_by_descent">identity by descent</a>” or “identity by state”? The former derives from real genealogical relatedness while the latter could signal genetic similarity due to chance inheritance of a similar profile of common variants – presumably enriched in cases by those variants causing disease. (That is of course what GWAS look for).<span style="mso-spacerun: yes;">&nbsp;&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">If the genetic similarity represents real, but distant relatedness, then how is this genetic similarity distributed across the genome, between any two pairs? The <a href="http://www.ncbi.nlm.nih.gov/pubmed/23667324">expectation</a> is that it would be present mainly in just one or two genomic segments that happen to have been passed down to both people from their distant common ancestor. However, that is likely to track a slight increase in identity by state as well, due to subtle population/deep pedigree structure. Graham Coop put it this way in an email to me: “</span><span lang="EN-GB" style="font-family: Calibri; font-size: 11.0pt; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Pairs of individuals with subtly higher IBS genome-wide are slightly more related to each other, and so slightly more likely to share long blocks of IBD.”</span><span lang="EN-GB"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">If we are really dealing with members of a huge extended pedigree (with many sub-pedigrees within it) – which is essentially what the human population is – then increased phenotypic similarity could in theory be due to either common or rare variants shared between distant relatives. (They would be different rare variants in different pairs).<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So, overall, it’s very unclear (to me at least) what is driving this tiny increase in mean genetic similarity among cases. It certainly seems like there is a lot more information in those matrices of relatedness (or in the data used to generate them) than is actually used – information that may be very relevant to interpreting what this effect means. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Nevertheless, this figure of slightly increased mean genetic similarity can be fed into models to extrapolate the heritability explained – i.e., how much of the genetic effects on predisposition to this disease can be tracked by that distant relatedness. I don’t know how this model works, mathematically speaking. But there are a number of assumptions that go into it that are interesting to consider. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">First, the most obvious explanation for an increased mean genetic similarity among cases is that they are drawn from a slightly different sub-population than controls. This kind of cryptic <a href="http://en.wikipedia.org/wiki/Population_stratification">population stratification</a> is impossible to exclude in ascertainment methods and instead must be mathematically “corrected for”. So, we can ask, is this correction being applied appropriately? Maybe, maybe not – there certainly is <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=21763486">not universal agreement</a> among the Illuminati on how this kind of correction should be implemented or how successfully it can account for cryptic stratification. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The usual approach is to apply <a href="http://en.wikipedia.org/wiki/Principal_components_analysis">principal components analysis</a> to look for global trends that differentiate the genetic profiles of cases and controls and to exclude those effects from the models interpreting real heritability effects. Lee and colleagues go to great lengths to assure us that these effects have been controlled for properly, excluding up to 20 components. <a href="http://www.ncbi.nlm.nih.gov/pubmed/23052944">Not everyone agrees</a> that these approaches are sufficient, however. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://bradenbost.wordpress.com/2011/06/21/lets-get-something-straight-cousins/" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://bradenbost.wordpress.com/2011/06/21/lets-get-something-straight-cousins/ " border="0" height="250" src="http://4.bp.blogspot.com/-htgM3-WufrQ/UnvRN30xqmI/AAAAAAAAAgk/lZxCJNkmfoM/s400/cousins.jpg" width="400" /></a></div><div class="MsoNormal"><span lang="EN-GB">Another major complication is that the relative number of cases and controls analysed does not reflect the prevalence of the disease in the population. In these studies, there were about equal numbers of each in fact, versus a 1:100 ratio of cases to controls in the general population for disorders like schizophrenia or autism. Does this skewed sampling affect the results? One can certainly see how it might. If you are looking to measure an effect where, say, the fifth cousin of someone with schizophrenia is very, very slightly more likely to have schizophrenia than an unrelated person, then ideally you should sample all the people in the population who are fifth cousins and see how many of them have schizophrenia. (This effect is expected to be almost negligible, in fact. We already know that even first cousins have only a modestly increased risk of 2%, from a population baseline of 1%. So going to fifth cousins, the expected effect size would likely only be around 1.0-something, if it exists at all).</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">You’d need to sample an awful lot of people at that degree of relatedness to detect such an effect, if indeed it exists at all. GCTA analyses work in the opposite direction, but are still trying to detect that tiny effect. But if you start with a huge excess of people with schizophrenia in your sample, then you may be missing all the people with similar degrees of relatedness who did not develop the disease. This could certainly bias your impression of the effect of genetic relatedness across this distance. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Lee and colleagues raise this issue and spend a good deal of time developing new methods to statistically take it into account and correct for it. Again, I cannot evaluate whether their methods really accomplish that goal. Generally speaking, if you have to go to great lengths to develop a novel statistical correction for some inherent bias in your data, then some reservations seem warranted. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So, it seems quite possible, in the first instance, that the signal detected in these analyses is an artefact of cryptic population substructure or ascertainment. But even if it we take it as real, it is far from straightforward to divine what it means. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The model used to extrapolate heritability explained has a number of other assumptions. First, is that all genetic interactions are <a href="http://en.wikipedia.org/wiki/Additive_genetic_effects">additive</a> in nature. [See <a href="http://www.wiringthebrain.com/2013/07/no-gene-is-island.html">here</a> for arguments why that is unlikely to reflect biological reality]. Second, it assumes that the relationship between genetic relatedness and phenotypic similarity is linear and can be extrapolated across the entire range of relatedness. At least, all you are supposedly measuring is the tiny effect at extremely low genetic relatedness – can this really be extrapolated to effects at close relatedness? We’ve already seen that this relationship is not linear as you go from twins to siblings to first cousins – those were the data used to argue for a polygenic architecture in the first place. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This brings us to the <a href="http://www.ncbi.nlm.nih.gov/pubmed/22269335">final assumption</a> implicit in the mathematical modelling – that the observed highly discontinuous distribution of risk to schizophrenia actually reflects a quantitative trait that is continuously (and normally) distributed across the whole population. A little sleight of hand can convert this continuous distribution of “liability” into a discontinuous distribution of cases and controls, by invoking a threshold, above which disease arises. While genetic effects are modelled as exclusively linear on the liability scale, the supposed threshold actually represents a sudden explosion of <a href="http://en.wikipedia.org/wiki/Epistasis">epistasis</a>. With 1,000 risk variants you’re okay, but with say 1,010 or 1,020 you develop disease. That’s non-linearity for free and I’m <a href="http://www.ncbi.nlm.nih.gov/pubmed/22269335">not buying it</a>. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">I also don’t buy an even more fundamental assumption – that the diagnostic category we call “schizophrenia” is a unitary condition that defines a singular and valid biological phenotype with a common etiology. Of course we know it isn’t – it is a diagnosis of exclusion. It simply groups patients together based on a similar profile of superficial symptoms, but does not actually imply they all suffer from the same condition. It is a place-holder, a catch-all category of convenience until more information lets us segregate patients by causes. So, the very definition of cases as a singular phenotypic category is highly questionable. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Okay, that felt good. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">But still, having gotten those concerns off my chest, I am not saying that the conclusions drawn from the GCTA analyses of disorders like schizophrenia and autism are not valid. As I’ve said repeatedly here, I am not qualified to evaluate the statistical methodology. I do question the assumptions that go into them, but perhaps all those reservations can be addressed. More broadly, I question the easy acceptance in the field of these results as facts, as opposed to the provisional outcome of arcane statistical exercises, the validity of which remains to be established.&nbsp;</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><span lang="EN-GB" style="font-family: Cambria; font-size: 12.0pt; mso-ansi-language: EN-GB; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-bidi-language: AR-SA; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-fareast-language: EN-US; mso-hansi-theme-font: minor-latin;">“<i>Facts are stubborn things, but statistics are pliable</i>.” – Mark Twain</span><br /><br /><span lang="EN-GB" style="font-family: Cambria; font-size: 12.0pt; mso-ansi-language: EN-GB; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-bidi-language: AR-SA; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-fareast-language: EN-US; mso-hansi-theme-font: minor-latin;">&nbsp;</span> http://www.wiringthebrain.com/2013/11/the-dark-arts-of-statistical-genomics.htmlnoreply@blogger.com (Kevin Mitchell)19tag:blogger.com,1999:blog-6146376483374589779.post-3486024881697991871Sun, 03 Nov 2013 18:08:00 +00002013-11-03T10:08:08.613-08:00cortexDTIfMRIimagingneuroimagingperceptionstructural imagingsynaesthesiasynesthesiaVBMPopping the hood on synaesthesia – what’s going on in there?<div dir="ltr" style="text-align: left;" trbidi="on"><div class="separator" style="clear: both; text-align: center;"><a href="http://www.roojoom.com/u/jyashan999,333/synesthesia-colourful-numbers-tasty-music-loud-food,1560" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.roojoom.com/u/jyashan999,333/synesthesia-colourful-numbers-tasty-music-loud-food,1560" border="0" height="320" src="http://4.bp.blogspot.com/-pfhoQmEIpas/UnaPGCIApaI/AAAAAAAAAfI/xELCXJIBbFM/s320/synesthesia-5.jpg" width="226" /></a></div><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoCommentText, li.MsoCommentText, div.MsoCommentText {mso-style-unhide:no; mso-style-link:"Comment Text Char"; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-IE;} span.CommentTextChar {mso-style-name:"Comment Text Char"; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:"Comment Text"; font-family:"Times New Roman"; mso-ascii-font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-hansi-font-family:"Times New Roman"; mso-bidi-font-family:"Times New Roman"; mso-ansi-language:EN-IE;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style></div>--&gt;<span lang="EN-GB">Synaesthesia – a “mixing of the senses” – was a popular scientific topic in the late 19<sup>th</sup> century, but fell out of favour during the mid-20<sup>th</sup> century, mainly due to the influence of behaviorism, which held that subjective experience was not a suitable subject for serious science. The start of this century has seen resurgence in interest in the topic, partly fuelled by the hope that <a href="http://en.wikipedia.org/wiki/Neuroimaging">neuroimaging</a>would provide objective measures of what is happening in the brains of people during synaesthetic experiences. </span> <div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">We (Erik O’Hanlon, Fiona Newell and myself) have recently published our own <a href="http://www.frontiersin.org/journal/10.3389/fpsyg.2013.00755/abstract">neuroimaging study</a> of synaesthesia, combining structural and functional analyses. Some of what follows is pulled from that paper, which contains references to the many studies cited below. Many of the ideas below are also discussed in a chapter I wrote for the new <a href="http://www.amazon.com/Oxford-Handbook-Synesthesia-Julia-Simner/dp/0199603324">Oxford Handbook of Synaesthesia</a>: <b style="mso-bidi-font-weight: normal;">Synaesthesia and cortical connectivity – a neurodevelopmental perspective. </b></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The term <a href="http://en.wikipedia.org/wiki/Synaesthesia">synaesthesia</a> refers both to the experience of some kind of cross-activation from one sense to another (but see more below) and to the condition of being prone to such experiences. It can be caused acutely in some people by drugs like <a href="http://en.wikipedia.org/wiki/Lysergic_acid_diethylamide">LSD</a> or <a href="http://en.wikipedia.org/wiki/Psilocybin">psilocybin</a>, which can famously induce visual experiences in response to music. It can also arise, very rarely, <a href="http://www.sciencedaily.com/releases/2013/07/130730101744.htm">due to brain injuries</a>, which leave one part of the brain without its normal innervation, causing invasion of neighbouring nerve fibres and a rewiring of the source of activation of a region, while the “meaning” of its activation remains the same. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Both of those types differ in many aspects from what is known as <a href="http://www.ncbi.nlm.nih.gov/pubmed/20939943">developmental synaesthesia</a>. This is a heritable condition in which particular stimuli generate specific and consistent additional sensory <a href="http://www.thefreedictionary.com/percept">percepts</a> or associations in another <a href="http://en.wikipedia.org/wiki/Stimulus_modality">sensory modality</a> or processing stream. Easy for me to say, I know – that is such a mouthful because it has to encompass many different forms. These include seeing letters or words in colour or associating them with colours, seeing colours in response to sounds (typically words or music), tasting words, feeling tastes as tactile sensation, associating numbers or calendar units with spatial locations and many others. It is surprisingly common, with between 1 and 4% of the population estimated to have the condition. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Though originally defined as a cross-<i style="mso-bidi-font-style: normal;">sensory</i> phenomenon, many cases involve more conceptual inducing stimuli (“inducers”) or resultant percepts (“concurrents”). Synaesthesia may thus be better <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=mitchell+kj+curiouser">thought of</a> as the association of additional attributes into what some psychologists call the “<a href="http://en.wikipedia.org/wiki/Schema_%28psychology%29">schema</a>” of the inducing object. Thus, the schema of the letter “A” would incorporate not only its particular shapes and sounds, but also the fact that it is, say, olive-green. Middle C may smell of oranges, Wednesday may be located behind a person’s head and the word “shed” may taste of boiled cabbage – these kinds of associations are idiosyncratic but highly stable in individual synaesthetes. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><div class="separator" style="clear: both; text-align: center;"><a href="http://blogs.scientificamerican.com/literally-psyched/2013/02/26/from-the-words-of-an-albino-a-brilliant-blend-of-color/" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://blogs.scientificamerican.com/literally-psyched/2013/02/26/from-the-words-of-an-albino-a-brilliant-blend-of-color/" border="0" height="287" src="http://2.bp.blogspot.com/-8cv32eo_UCs/UnaQ4iX31JI/AAAAAAAAAfc/spl7mMyQ_4c/s320/synaesthesia+alphabet.jpg" width="320" /></a></div><span lang="EN-GB">The mechanism driving these additional percepts or associations is unknown, though most researchers agree it is likely related to functions in the cerebral cortex. This is the part of the brain where <a href="http://www.ncbi.nlm.nih.gov/pubmed/17964253">specialised areas emerge</a> that are dedicated to processing the kinds of stimuli that often induce synaesthetic experiences or associations – such as letters, words, musical notes, numbers, calendar units. These are specialised categories, each with many different members, which are learned through experience. As a child has repeated exposures to stimuli such as letters, a <a href="http://en.wikipedia.org/wiki/Visual_word_form_area">particular part</a>of the visual cortex becomes specialised for processing them, showing more and more selective responses for letters with greater experience. That region not only becomes more responsive to letters, it becomes less responsive to other stimuli. Also, learning has to sharpen the representations of each letter, so that all the various forms of the letter “A” are recognised as such, while simultaneously being distinguished from “D”, “R”, and other visually similar graphemes. In addition, the shapes for “A” have to be linked to the various sounds that it can make, in different contexts. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In contrast to the inducing stimuli, the concurrent percepts associated with the synaesthetic experience tend to be much simpler: colours, tastes, textures, spatial locations. These perceptual primitives are also typically processed by specialised circuits or areas of the cortex, but ones that mature much earlier and that develop in a manner that is not so strictly driven by experience. For example, a particular area of the <a href="http://en.wikipedia.org/wiki/Visual_cortex">visual cortex</a>, called V4, is selectively involved in processing colour: this area is strongly activated by coloured stimuli; if it is stimulated with an electrode, patches of colour may be seen in the visual field; and, finally, damage to V4 can lead to complete colour blindness. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So, a simple model for what is happening in synaesthesia is that activation of one cortical area by an inducing stimulus (say, letters), aberrantly and consistently <a href="http://www.wiringthebrain.com/2012/09/the-grand-schema-things.html">causes co-activation</a> of another cortical area (say, the colour area), leading to an additional colour percept or association. Neuroimaging seems like the perfect way to test this hypothesis – if true, we should be able to see additional areas “lighting up” in functional magnetic resonance imaging (<a href="http://en.wikipedia.org/wiki/Functional_magnetic_resonance_imaging">fMRI</a>) scans when synaesthetes are exposed to stimuli that induce a synaesthetic experience. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span lang="EN-GB">By now, about a <a href="http://www.google.ie/url?sa=t&amp;rct=j&amp;q=&amp;esrc=s&amp;source=web&amp;cd=6&amp;sqi=2&amp;ved=0CFsQFjAF&amp;url=http%3A%2F%2Fwww.daysyn.com%2FRouwetal2011.pdf&amp;ei=w4R2UqzgGKyu7AaMuIHICg&amp;usg=AFQjCNG9VvyLQAjzL9CHoML8Ltgkge7JxQ&amp;sig2=yn_06eYFfX1ZRuzxkyQnLg&amp;bvm=bv.55819444,d.ZGU">dozen functional neuroimaging experiments</a> have been performed to try to define the neural correlates of synaesthetic experiences. Most of these have studied subjects with <a href="http://en.wikipedia.org/wiki/Grapheme%E2%80%93color_synesthesia">grapheme-colour</a> or sound-colour synaesthesia and many have looked specifically for activation of V4 or other visual areas in response to the presentation of the “inducer” – either aurally presented sounds or visually presented achromatic graphemes. These have indeed provided some insights into the neural basis of synaesthesia but their findings are surprisingly variable.</span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span lang="EN-GB">Some of them have reported exactly the expected observation – extra activation of regions such as V4. However, it is not at all clear that such an effect can be taken as a ground truth, as other studies have not observed this but have seen activation or functional connectivity differences in other visual areas or in other brain regions, such as <a href="http://en.wikipedia.org/wiki/Parietal_cortex">parietal cortex</a>. Still others have observed no additional activation correlating with the synaesthetic experience at all. One early <a href="http://en.wikipedia.org/wiki/Positron_emission_tomography">positron emission tomography</a> (PET) study even found, in addition to some areas of extra activation in coloured-hearing synaesthetes, greater cortical <i style="mso-bidi-font-style: normal;">deactivation</i> in other areas in response to spoken words that induced a synaesthetic experience of colour. </span></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span lang="EN-GB">What is going on in the brain of synaesthetes during a synaesthetic experience thus remains very much an open question. Phenotypic heterogeneity may explain some of the variation in these results – perhaps all of the results are “right” and mechanisms differ across synaesthetes in different studies. Even if that is the case, a simple model of excess cross-activation between highly restricted cortical areas seems too minimal to accommodate all these findings. Rather, these findings suggest that differences in connectivity may be quite extensive in the brains of synaesthetes, a hypothesis which is supported by structural neuroimaging studies.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">These studies have been performed to try and identify anatomical correlates of the <i style="mso-bidi-font-style: normal;">condition</i>of synaesthesia (as opposed to the fMRI experiments which are looking at the <i style="mso-bidi-font-style: normal;">experience</i> of synaesthesia). They aimed to test the hypothesis that cortical modularity breaks down in people with synaesthesia due to the presence of additional anatomical connections between normally segregated cortical areas. (The alternative type of model proposes altered neurochemistry, leading to disinhibition of normally existing connections). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Here, the findings are somewhat more consistent, at least on a general level. <a href="http://www.google.ie/url?sa=t&amp;rct=j&amp;q=&amp;esrc=s&amp;source=web&amp;cd=6&amp;sqi=2&amp;ved=0CFsQFjAF&amp;url=http%3A%2F%2Fwww.daysyn.com%2FRouwetal2011.pdf&amp;ei=w4R2UqzgGKyu7AaMuIHICg&amp;usg=AFQjCNG9VvyLQAjzL9CHoML8Ltgkge7JxQ&amp;sig2=yn_06eYFfX1ZRuzxkyQnLg&amp;bvm=bv.55819444,d.ZGU">Several studies</a> have now identified structural differences in the brains of synaesthetes compared to controls. In almost all cases, synaesthetes showed greater volumes of areas of grey or white matter or greater "<a href="http://en.wikipedia.org/wiki/Fractional_anisotropy">fractional anisotropy</a>" within certain white matter tracts than controls. Some of these differences are in the general region of visual areas thought to be involved in the synaesthetic experience but others are more widespread, in parietal or even frontal regions. A recent study analysed global connectivity patterns in the brains of synaesthetes, using networks derived from correlations in cortical thickness. The global network topology was significantly different between synaesthetes and controls, with synaesthetes showing increased clustering, suggesting global hyperconnectivity. The differences driving these effects were widespread and not confined to areas hypothesised to be involved in the grapheme-colour synaesthetic experience itself. Widespread functional connectivity differences have also been observed in a study using resting-state fMRI.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">There is thus a strong general trend: the brains of groups of synaesthetes do show structural differences to those of groups of controls, these are concentrated in <a href="http://en.wikipedia.org/wiki/Occipital_lobe">occipital</a> and <a href="http://en.wikipedia.org/wiki/Temporal_lobe">temporal</a> regions but extend also to <a href="http://en.wikipedia.org/wiki/Parietal_lobe">parietal</a> and <a href="http://en.wikipedia.org/wiki/Frontal_lobe">frontal</a> lobes, and they almost always involve increases in the measured parameters in synaesthetes. Though the exact locations of such differences vary between studies, the fact that they all agree in the direction of the effects strongly argues that they represent a real, generalizable finding. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">If only we knew what it meant. It could mean that the primary cause of synaesthesia is really a structural difference in the brain. However, the imaging parameters measured (like volume of some cluster of grey matter or fractional anisotropy of a white matter tract) are really quite crude and influenced by many variables at a cellular neuroanatomical level. What has not yet emerged is tractography evidence showing an example of connections that are clearly not present in non-synaesthetes. It is thus not obvious how the observed structural differences can explain the synaesthetic experience. It could just as well be that structural differences are secondary and arise due to a lifetime of altered activity patterns in the neural circuits involved. Or the structural differences might be entirely unrelated to the experience of synaesthesia and reflect instead some broader phenotypes associated with the condition. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">With this as background, we designed a neuroimaging study aimed at probing the functional involvement in the synaesthetic experience of areas with structural differences. What we found surprised us. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><div class="separator" style="clear: both; text-align: center;"><a href="http://3.bp.blogspot.com/-ClntZufot6Y/UnaP0yCUuQI/AAAAAAAAAfQ/8liaYwP0Ww8/s1600/Figure3_Structural_and_FA.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="640" src="http://3.bp.blogspot.com/-ClntZufot6Y/UnaP0yCUuQI/AAAAAAAAAfQ/8liaYwP0Ww8/s640/Figure3_Structural_and_FA.jpg" width="480" /></a></div><span lang="EN-GB">We compared a group of 13 synaesthetes with a group of 11 controls (decent sample sizes for this field, but more on that below). First we looked for average structural differences between the members of these two groups. Using a method called <a href="http://en.wikipedia.org/wiki/Voxel-based_morphometry">voxel-based morphometry</a>, we identified multiple clusters of increased volume of either grey or white matter in the synaesthetes compared to controls. We also used <a href="http://en.wikipedia.org/wiki/Diffusion-weighted_imaging#Diffusion-weighted_imaging">diffusion-weighted imaging</a> to look at the structural parameters of nerve fibres and found multiple regions of increased fractional anisotropy in synaesthetes compared to controls. Similar to previous studies, these structural differences were concentrated in but not exclusive to the back of the brain (occipital and temporal lobes) and were all increases in synaesthetes. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">So far, so good – these results generally replicate and extend previous findings. We then used fMRI to investigate how the areas showing a structural difference responded to stimuli that induce a synaesthetic experience. All the synaesthetes in the study had grapheme-colour synaesthesia – they attribute colours to letters of the alphabet. We showed them images of letters or of non-meaningful characters, as a contrast, and examined responses in nine areas of increased grey matter volume. Four of those areas showed a differential response to this contrast, in synaesthetes but not in controls (a “group by condition interaction”). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><div class="separator" style="clear: both; text-align: center;"><a href="http://3.bp.blogspot.com/-kkv9yX6SMdk/UnaOYJJShMI/AAAAAAAAAe8/-nO7fgn7ugw/s1600/Figure4_GMROIs_with_fMRI.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" height="320" src="http://3.bp.blogspot.com/-kkv9yX6SMdk/UnaOYJJShMI/AAAAAAAAAe8/-nO7fgn7ugw/s320/Figure4_GMROIs_with_fMRI.jpg" width="240" /></a></div><span lang="EN-GB">When we looked more closely at the responses in these areas we found something really surprising. Two of them showed a clear difference in response to letters, but this was driven by a very strong <i style="mso-bidi-font-style: normal;">reduction</i> in activity in synaesthetes. Not only was the BOLD (<a href="http://en.wikipedia.org/wiki/Blood-oxygen-level_dependent">blood oxygen level-dependent</a>) signal lower than in controls, it was lower than baseline in those voxels. There is good evidence that negative BOLD signals of this type reflect cortical <i style="mso-bidi-font-style: normal;">deactivations</i> – a suppression of neuronal activity in that region. None of the areas showed a greater response to letters in synaesthetes. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">We also performed an unbiased, whole-brain analysis with the same contrast, again expecting to find regions with an increased selective response to letters in synaesthetes. We found fourteen areas showing a group by condition interaction, but none of these were driven by increased activation to letters in synaesthetes. Three of them were driven by negative BOLD responses in synaesthetes (these did not overlap the areas with grey matter volume differences). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">What does this all mean? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">My first thought, and I hope it is yours too, is: “possibly nothing”. After all, these are unexpected results from exploratory analyses. While they are corrected for multiple tests, they still could represent a false positive observation – a statistical blip that occurred in that experiment, with that sample, that does not represent a generalizable finding. This is a problem that dogs the fMRI literature and there is only one solution to it – replication, replication, replication! Because our study was designed as at least a conceptual replication and extension of previous findings, we did not include a separate replication sample. (It was honestly also partly because the field does not demand it). If we were designing a similar study today, I would certainly aim for a larger sample and an independent replication sample (and would hope that funding agencies would begin to apply these standards more rigorously). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Actually though, this finding is not completely novel – cortical deactivations were previously reported in response to synaesthesia-inducing stimuli in a PET study, some in the same areas we observe. Whether they have occurred in other fMRI studies is a little hard to know – experimental designs focusing on specific regions or looking specifically for positive differences may have missed these kinds of effects. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The idea that cortical deactivations might be involved in synaesthetic experiences is also neither unprecedented nor outlandish. Here’s what we say in the paper:</span></div><div class="MsoNormal"><br /></div><div class="MsoCommentText" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><span lang="EN-IE" style="font-family: Cambria; mso-ascii-theme-font: minor-latin; mso-hansi-theme-font: minor-latin;">“One possible, though speculative, explanation for these observations relates to the fact that the synaesthetic percept or association is internally generated and often reported as being “in the mind’s eye”. A number of studies have shown that generation of an internal sensory representation induces deactivation of regions which might compete for attention or provide conflicting information. For example, visual imagery induces negative BOLD in auditory cortex, verbal memory induces deactivation across auditory and visual cortices and imagery of visual motion induces deactivation of early visual cortices (V1-3). <a href="http://www.ncbi.nlm.nih.gov/pubmed/16337922">Amedi and colleagues</a>found a strong correlation across subjects between the deactivation of auditory cortex during visual mental imagery and their score on the vividness of visual imagery questionnaire (VVIQ). We have <a href="http://www.ncbi.nlm.nih.gov/pubmed/17627844">previously reported</a> that synaesthetes tend to score higher on this imagery measure. This is not to suggest that the synaesthetic percepts arise from the same processes as mental imagery per se – there is evidence from functional imaging that this is not the case. But it is possible that the vividness of a mental image and of a synaesthetic percept both rely on deactivation of other areas.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoCommentText" style="mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;"><br /></div><div class="MsoNormal"><span lang="EN-GB">Such a conclusion is supported by findings from a <a href="http://en.wikipedia.org/wiki/Transcranial_direct-current_stimulation">transcranial direct current stimulation</a> (tDCS) study. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><div class="separator" style="clear: both; text-align: center;"><a href="http://www.nature.com/npp/journal/v35/n1/full/npp200987a.html#fig5" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="http://www.nature.com/npp/journal/v35/n1/full/npp200987a.html#fig5" border="0" height="161" src="http://2.bp.blogspot.com/-RIRzJnM5GOM/UnaN1VcUS-I/AAAAAAAAAe0/-VmUac1Yq9Y/s320/tDCS.jpg" width="320" /></a></div><span lang="EN-GB">[This technique basically hooks up a 9-volt battery to electrodes on your scalp, and applies small zaps of current in particular patterns. It can be applied to affect particular regions and to either activate them or inhibit them. Activating motor cortex can cause muscle movements while activating visual cortex can cause perception of winking lights or “phosphenes” in the visual field].</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB"><a href="http://www.ncbi.nlm.nih.gov/pubmed/22100060">Terhune and colleagues</a> found that synaesthetes showed enhanced cortical excitability of primary visual cortex, with a 3-fold lower phosphene detection threshold in response to activation by tCDS. [This finding is consistent with a <a href="http://www.ncbi.nlm.nih.gov/pubmed/18723094">previous study</a> from our own group using <a href="http://en.wikipedia.org/wiki/Electroencephalography">electroencephalography</a>, which found that the amplitude of early visual evoked potentials was larger in synaesthetes compared to controls, even in response to very simple visual stimuli that did not induce a synaesthetic experience]. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">They tested whether this hyperexcitability of primary cortex could be either a contributing source to the generation of the synaesthetic percept, or, alternatively, a competing signal, which would interfere with the conscious perception of the synaesthetic percept. They show strong evidence that the latter is the case – stimulation or inhibition of primary visual cortical activity diminished or enhanced, respectively, the synaesthetic experience, based on both self-reports and behavioural interference measures. It thus seems plausible that the cortical deactivations we observe in response to stimuli that induce the synaesthetic experience could be an important part of that response, possibly involved in reducing the signals of competing percepts and allowing the internally generated synaesthetic percept to reach conscious awareness.”</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Future studies will hopefully tell whether these kinds of cortical deactivations really are an important component of the synaesthetic experience. For now, our findings add to a quite varied set of neuroimaging findings, which have yet to definitively nail down the neural correlates of the synaesthetic experience. Perhaps expecting a single mechanism is a mistake – if the condition is really heterogeneous we may need some other means (like genetics perhaps) to segregate subjects and elucidate the neural underpinnings of this fascinating condition. </span></div><div class="MsoNormal"><br /></div>http://www.wiringthebrain.com/2013/11/popping-hood-on-synaesthesia-whats.htmlnoreply@blogger.com (Kevin Mitchell)5tag:blogger.com,1999:blog-6146376483374589779.post-2430833776081358331Mon, 02 Sep 2013 11:47:00 +00002013-09-02T06:18:19.011-07:00cell typesconnectivityneural circuitsneurogeneticsoptogeneticspsychiatricWhy optogenetics deserves the hype <div dir="ltr" style="text-align: left;" trbidi="on"><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1791491579 18 0 131231 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; mso-themecolor:hyperlink; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} p.MsoListParagraph, li.MsoListParagraph, div.MsoListParagraph {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraphCxSpFirst, li.MsoListParagraphCxSpFirst, div.MsoListParagraphCxSpFirst {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraphCxSpMiddle, li.MsoListParagraphCxSpMiddle, div.MsoListParagraphCxSpMiddle {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} p.MsoListParagraphCxSpLast, li.MsoListParagraphCxSpLast, div.MsoListParagraphCxSpLast {mso-style-priority:34; mso-style-unhide:no; mso-style-qformat:yes; mso-style-type:export-only; margin-top:0in; margin-right:0in; margin-bottom:0in; margin-left:.5in; margin-bottom:.0001pt; mso-add-space:auto; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} /* List Definitions */ @list l0 {mso-list-id:1192456877; mso-list-type:hybrid; mso-list-template-ids:-1555376632 67698703 67698713 67698715 67698703 67698713 67698715 67698703 67698713 67698715;} @list l0:level1 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level2 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level3 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level4 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level5 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level6 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} @list l0:level7 {mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level8 {mso-level-number-format:alpha-lower; mso-level-tab-stop:none; mso-level-number-position:left; text-indent:-.25in;} @list l0:level9 {mso-level-number-format:roman-lower; mso-level-tab-stop:none; mso-level-number-position:right; text-indent:-9.0pt;} ol {margin-bottom:0in;} ul {margin-bottom:0in;} </style> <span lang="EN-GB"><a href="http://en.wikipedia.org/wiki/Optogenetics">Optogenetics</a> has come in for <a href="http://blogs.scientificamerican.com/cross-check/2013/08/20/why-optogenetic-methods-for-manipulating-brains-dont-light-me-up/">some stick</a> lately, with a number of people criticising the hype that this technique generates in some quarters. That’s fair enough, I suppose – there have no doubt been some claims made about what can be accomplished with this technique that are, at the very least, premature. I’m all for bashing hype (see The Trouble with Epigenetics <a href="http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-1.html">1</a>and <a href="http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-2.html">2</a>, for example), but criticising the technique for what it’s not good for seems to be missing the point to me. </span> <br /><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">To me, optogenetics will revolutionise neuroscience. It is the tool that will finally let us meaningfully integrate the cellular with the systems level. Not by itself, of course – we’ll still need all the electrophysiology and pharmacology and neuroimaging and lesion studies and model organisms and whatever you’re having yourself. And not without some teething problems and over-interpretation of early findings, which will no doubt earn more tongue-lashings from the hype-police. But it will let us ask questions we have not been able to ask before – the right questions, at the level of cell types, the fundamental functional units of the nervous system. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://neurobyn.blogspot.se/2011/01/controlling-brain-with-lasers.html" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" height="223" src="http://2.bp.blogspot.com/-HndJXrDzaXw/UiR3bVxoiYI/AAAAAAAAAdU/tN586HRWeKI/s320/Optogenetics.jpg" width="320" /></a></div><div class="MsoNormal"><span lang="EN-GB">Before I go on, a brief primer on how optogenetics works: this technique takes advantage of a number of <a href="http://en.wikipedia.org/wiki/Channelrhodopsin">proteins</a> found in various species of algae that respond to light of certain wavelengths by opening a channel in their cell membrane to allow electrochemical ions (like sodium or chloride) to flow in or out of the cell. Controlling the flow of such ions along their fibres is also how neurons conduct electricity. If you take the gene that encodes the light-sensitive channel from algae and force neurons to express it, then they will become responsive to light – if you shine a light on them they will “fire” an electrical signal, or “<a href="http://en.wikipedia.org/wiki/Action_potential">action potential</a>”. If you turn the light off, they will stop firing action potentials. And if you use a different channel protein, you can silence the neurons and stop them firing action potentials. This gives very tight, reversible control over the activity patterns of the neurons expressing these channel proteins (called <a href="http://en.wikipedia.org/wiki/Channelrhodopsin">channelrhodopsins</a>). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://4.bp.blogspot.com/-OPUvR3CGLrc/UiR35qgj_hI/AAAAAAAAAdk/G71CfXvZDjk/s1600/Optogenetics-optic+fibre.jpg" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img border="0" height="274" src="http://4.bp.blogspot.com/-OPUvR3CGLrc/UiR35qgj_hI/AAAAAAAAAdk/G71CfXvZDjk/s320/Optogenetics-optic+fibre.jpg" width="320" /></a><span lang="EN-GB">The trick, and the power of the technique, comes from the specificity with which you can direct that expression. This is based on the fact that different types of cells express different sets of genes. All genes have two main parts – one part is basically the recipe or code for a particular protein. The other part, which is encoded on a neighbouring piece of DNA, is the <a href="http://en.wikipedia.org/wiki/Regulatory_region">regulatory region</a>– the instructions for when and where to make that protein and how much to make. Those two regions can be separated. You can cut out the DNA that makes up just the regulatory piece of one gene and hook it up to the protein-coding region for any other gene you like (in this case, a channelrhodopsin protein). Now you can take that fusion gene and introduce it to cells or transgenically introduce it to animals, like worms or flies or mice. Such animals will now express channelrhodopsin only in the cell types directed by the regulatory piece of DNA you chose. A variety of other molecular methods can also be used to achieve this goal, including <a href="http://www.ncbi.nlm.nih.gov/pubmed/21943598">resources</a> based on binary systems like the <a href="http://en.wikipedia.org/wiki/Cre-Lox_recombination">Cre-LoxP</a> recombinase system. (Fibre optics can then be used to target light to those cells in particular brain regions).</span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://scientopia.org/blogs/bridgeblog/2010/10/22/can-you-cajal/" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" height="320" src="http://1.bp.blogspot.com/-gMuhxw0ZVIE/UiR4E8jK3vI/AAAAAAAAAds/by7dLXwpfEU/s320/Cajal+cell+types.jpg" width="243" /></a></div><div class="MsoNormal"><span lang="EN-GB">So how many different cell types are we talking about? Going by the kinds of animations common in science fiction movies, many people apparently think of the inside of the brain as a network of effectively identical cells, randomly placed in a sponge-like layout, connecting simply to their nearest neighbours. Nothing could be further from the truth. We have known since the time of <a href="http://en.wikipedia.org/wiki/Ramon_y_cajal">Ramon y Cajal</a> and <a href="http://en.wikipedia.org/wiki/Camillo_Golgi">Golgi</a> that there are many distinct types of neurons, which are distributed in a highly organised fashion in different brain regions and interconnected with exquisite specificity. And when I say many, I mean many hundreds, possibly thousands of types. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The <a href="http://en.wikipedia.org/wiki/Retina">retina</a> alone has over <a href="http://www.ncbi.nlm.nih.gov/pubmed/23083731">60 distinct</a>, recognised neuronal cell types and more subtypes are being defined all the time. Those 60 cell types are arranged in four or five distinct layers, with multiple subtypes in each layer. There are at least a <a href="http://www.ncbi.nlm.nih.gov/pubmed/20876118">dozen parallel pathways</a> across these several layers, processing various aspects of the visual stimulus – colour, form, direction, motion and many others. If you want to understand how the retina works – to reverse engineer it – you need to know what the functions of these cell types are within the context of the circuit in which they are embedded.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The importance of cell types as functional classes is blindingly obvious for the retina, but the same principle applies to any area of the brain. Subsets of cells in any area not only have discrete jobs to do within that area, making unique contributions to the computations carried out there, they also often connect in distinct, cell-type-specific, parallel circuits with other brain areas. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In the <a href="http://en.wikipedia.org/wiki/Cerebral_cortex">cerebral cortex</a>, different excitatory cell types are <a href="http://www.ncbi.nlm.nih.gov/pubmed/15217339">arranged</a> into six obvious layers, but these often have several sublayers. And within each layer, there are multiple subtypes of excitatory neuron, intermingled. In layer 5, for example, some neurons project across the corpus callosum to the other hemisphere, some within the cortex on their own side and others to subcortical targets. Each of these types contains multiple subclasses carrying information to distinct targets. That cellular complexity is multiplied by the number of cortical areas – subcortically-projecting layer 5 neurons in motor cortex are molecularly distinct from those in visual cortex, for example. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://2.bp.blogspot.com/-HhE5HAv66QM/UiR5Jvb9PuI/AAAAAAAAAd8/fHaV5cd-R30/s1600/cortical+cell+types-2.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="212" src="http://2.bp.blogspot.com/-HhE5HAv66QM/UiR5Jvb9PuI/AAAAAAAAAd8/fHaV5cd-R30/s640/cortical+cell+types-2.png" width="640" /></a></div><div class="separator" style="clear: both; text-align: center;"></div><br /><div class="MsoNormal"><span lang="EN-GB">And we haven’t even started on the <a href="http://www.scholarpedia.org/article/Interneurons%23Diversity_and_classification_of_cortical_inhibitory_interneurons">interneurons</a>. These are smaller, more locally projecting cells, which are inhibitory – they put the brakes on excitation in neural circuits. They not only prevent runaway excitation, but also, crucially, control many aspects of information processing, such as filtering, gain control and temporal and spatial integration. In addition, they orchestrate the synchronous firing of ensembles of excitatory neurons, which in turn is a central mechanism in mediating communication between brain areas. Just in the hippocampus, there are <a href="http://www.ncbi.nlm.nih.gov/pubmed/18599766">twenty-some subtypes</a> of interneurons already known, and, again, more are being defined all the time. Each of these subtypes is distributed in a particular manner, expresses different kinds of ion channels and neurotransmitter and neuromodulator receptors and makes specific kinds of synapses on specific subcellular locations of specific target cells. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.ncbi.nlm.nih.gov/pubmed/18599766"><img border="0" height="425" src="http://1.bp.blogspot.com/-oHmv8ilWAc4/UiR5xr8in_I/AAAAAAAAAeA/PDX3MsSfc8w/s640/Hippocampal+interneurons+copy-small.jpg" width="640" /></a></div><br /><div class="MsoNormal"><span lang="EN-GB">We cannot ignore this cellular complexity, but, until recently, we have had few options for really embracing it. As long ago as 1979, the central importance of cell types was recognised. <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020419">Francis Crick had seen</a> the power of molecular genetic techniques in other areas of biology and knew that, with the right tools in hand, it could be harnessed to help unlock the mysteries of the brain. </span><span style="mso-ansi-language: EN-US;">His article in Scientific American’s, <b>“Thinking about the Brain”</b>explicitly described three needed methods for neuroscience to make real progress: first, a method by which “<i>all the connections to a single neuron could be stained”;</i> second, a method by which <i>“all neurons of just one type could be inactivated, leaving the others more or less unaltered”; </i><span style="mso-bidi-font-style: italic;">and<i>,</i></span> third, a means to differentially stain each cortical area, <i>“so that we could see exactly how many there are, how big each one is and exactly how it is connected to other areas.”</i></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">While <a href="http://en.wikipedia.org/wiki/Connectomics">connectomics</a> on various scales is addressing the first and third of these, optogenetics provides the means to accomplish the second. Indeed, it surpasses the requirement Crick had in mind, by allowing not just inactivation but also activation, with exquisite temporal control and rapid reversibility. (As it happens, optogenetics is also a fantastic method for mapping functional connections between cell types). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Using optogenetics, we can move beyond the crude methods of lesion studies or stimulation with electrodes inserted into a particular brain region. These methods are hopelessly confounded by the intermingling of cell types within the targeted regions. In any given area, it is typical to find multiple cell types that directly antagonise each other – lesioning them all or stimulating them all may not reveal the complex functions and computations carried out by the region in question. Optogenetics simply provides a much more precise, selective and controllable method to perform these kinds of investigations. </span></div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://www.nature.com/neuro/journal/v14/n3/fig_tab/nn0311-277_F1.html" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" height="320" src="http://2.bp.blogspot.com/-MQiRNfMrDn8/UiR6P1b-UcI/AAAAAAAAAeI/S4SXTpP1dIw/s320/optogenetics-appetite.jpg" width="310" /></a></div><div class="MsoNormal"><span lang="EN-GB">One example is provided by the circuitry controlling appetite. The <a href="http://en.wikipedia.org/wiki/Arcuate_nucleus">arcuate nucleus</a>in the hypothalamus is a crucial hub in this signaling, integrating signals from the periphery, such as <a href="http://en.wikipedia.org/wiki/Leptin">leptin</a>and insulin levels, and passing these signals on to further hypothalamic regions which mediate feeding behaviours. Lesioning the arcuate nucleus has little effect on feeding behaviour, however. The reason for that was discovered once the leptin receptor and other players in this system were cloned and molecular genetic characterisations revealed two major cell types intermingled in the arcuate nucleus. These directly antagonise one another and communicate opposite signals to downstream areas – it is the balance between their activities which controls behaviour. Several <a href="http://www.ncbi.nlm.nih.gov/pubmed/22801496">recent</a>optogenetics <a href="http://www.ncbi.nlm.nih.gov/pubmed/21209617">studies</a>have now greatly increased our understanding of this system, mapping connectivity to specific cell types in downstream target regions, revealing the hierarchy of their functional relationships and directly demonstrating short- and longer-term effects on behaviour of activity of these different neuronal classes.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">These experiments are not just elegant and precise, they are powerful and incisive – they are the right experiments to do to understand this system because they interrogate the system at the right level: the distinct cell types that make up the fundamental computational units. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Another reason I am so excited by optogenetics is it provides one means to integrate analyses at very different levels, uniting what have been disparate areas of neuroscience. The characteristics of individual neurons or specific synaptic connections are traditionally analysed by molecular and cellular neuroscience and electrophysiology. The roles of specific neurotransmitters or receptors are probed with pharmacology. The functions and interactions of brain areas are studied using field recordings, electroencephalography, neuroimaging, lesions and other systems neuroscience methods. These approaches have traditionally been carried out by different people with different skills and different mindsets. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">While we may have learned a lot of details at each level, integrating knowledge across those levels has remained a huge challenge. As a result, we have had little real understanding of how the functions of any brain area emerge from the interactions of its component cells. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Optogenetics provides a method to connect those levels. By inhibiting or activating entire classes of neurons within a region and analysing the effects on activity in other cells or regions or the effects on behaviour of the animal, on a moment-to-moment basis, we can discern the functions which these cells and circuits have evolved to perform. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">And that’s the key, really – evolution has built the mammalian brain by elaborating on basic plans already present in our distant ancestors. In simpler organisms it is possible to identify not just types of cells, but individual neurons – in <a href="http://en.wikipedia.org/wiki/C_elegans">nematodes</a>, the 302 neurons have all been named. In insects, you can see the equivalent individual neurons repeated in each segment of the ventral nerve cord. Those nervous systems function based on the actions of individual neurons and their interconnections. Mammalian brains function more at the level of ensembles of neurons, but the basic logic is similar – evolution has built these brains by expanding the numbers of cells of ancestral types, so that what was once a single neuron is now a population of neurons of the same “type”. Evolution has also increased the <a href="http://www.ncbi.nlm.nih.gov/pubmed/18927580">diversity of subtypes</a>, which are deployed and combined in myriad ways to generate the incredibly complex circuitry we seek to understand.<span style="mso-spacerun: yes;">&nbsp; </span></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">That is the reason I argue that cell types are the fundamental units of the nervous system and why optogenetics is such a powerful method to help move neuroscience from crude and fragmented approaches to a united field capable of explaining how the operations of the mind emerge from the workings of the brain.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Let me add a few notes:</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">First of all, I don’t have a dog in this fight. I have no stake in any optogenetic technologies and don’t currently use the method, though I certainly hope to in the future. I’m simply really excited by its potential. I don’t get giddy over new techniques very often, but when I saw <a href="http://www.stanford.edu/group/dlab/about_pi.html">Karl Deisseroth</a>present his team’s work at the first <a href="http://conferences.wiringthebrain.com/2009-conference-details/">Wiring the Brain meeting in 2009</a>, I was blown away by its potential – along with the rest of the audience of hard-to-impress neuroscientists.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Second, optogenetics alone is not the answer to all things – it is a method that is suitable for asking specific kinds of questions. There are, in addition, numerous conceptually similar molecular genetic techniques now being used or developed, which greatly expand our arsenal of tools for monitoring and manipulating patterns of neuronal activity.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Third, let’s consider a few of the common and recent critiques of the method:</span></div><div class="MsoNormal"><br /></div><div class="MsoListParagraphCxSpFirst" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">1.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">The drivers we are using do not target real cell types, because they depend on the expression pattern of single genes, while real cell types are defined in a combinatorial fashion by the expression of multiple genes. That is absolutely true, but <a href="http://www.ncbi.nlm.nih.gov/pubmed/20699143">intersectional strategies</a> (which drive expression only where two genes intersect) are greatly increasing the specificity possible. Also, combining transgenic drivers with viral systems that can be delivered to specific brain regions can address many of these issues.</span></div><div class="MsoListParagraphCxSpMiddle"><br /></div><div class="MsoListParagraphCxSpLast" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">2.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">We don’t know what stimulation protocols to use. Just blasting some neurons so they fire like crazy does not recapitulate the real patterns of firing seen in vivo. Also true, though that criticism applies to traditional electrical stimulation as well. But molecular genetic tools designed to monitor and measure these patterns have also been developed and such patterns can be retransmitted through the sensitive, rapid and reversible optogenetic drivers.</span></div><div class="MsoNormal"><br /></div><div class="MsoListParagraph" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">3.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">It’s <a href="http://rxnm.wordpress.com/2012/11/16/neurons-do-not-have-onoff-switches/">not good for studying neuromodulation</a> – the slow signaling which is so important for changes in the functions of neural circuits over longer timeframes. This is just wrong. You just need to target the neuromodulatory neurons – the ones that release dopamine or serotonin in response to action potentials that they fire. Many of the most exciting early papers using optogenetics have taken this approach. In addition, new techniques, like <a href="http://www.ncbi.nlm.nih.gov/pubmed/23769625">DREADD</a>, have been developed to directly activate G-protein-coupled receptors in a way that closely mimics neuromodulatory effects. </span></div><div class="MsoNormal"><br /></div><div class="MsoListParagraph" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">4.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">It <a href="http://markgbaxter.wordpress.com/2013/08/21/on-optogenetics/">can’t replace lesion studies</a>. Yes, it can. Or at least it can provide a crucial complement. Lesion studies are great for studying the effects of lesions to specific areas (of obvious clinical importance) but limited for inferring how the functions of those areas are mediated, for the reasons outlined above.</span></div><div class="MsoNormal"><br /></div><div class="MsoListParagraph" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span lang="EN-GB" style="mso-bidi-font-family: Cambria; mso-bidi-theme-font: minor-latin; mso-fareast-font-family: Cambria; mso-fareast-theme-font: minor-latin;"><span style="mso-list: Ignore;">5.<span style="font: 7.0pt &quot;Times New Roman&quot;;">&nbsp;&nbsp;&nbsp;&nbsp; </span></span></span><span lang="EN-GB">We <a href="http://blogs.scientificamerican.com/cross-check/2013/08/20/why-optogenetic-methods-for-manipulating-brains-dont-light-me-up/">can’t use it for therapies</a> because we don’t know which brain regions to target. Well, first off, deep brain stimulation is currently in use for conditions like obsessive-compulsive disorder and Parkinson’s disease and is showing great promise for depression. Optogenetic approaches may provide a more sophisticated method to control neural activity, which is directed to specific cell types within the target region. This is likely a long way in the future and would involve the complex issue of transfecting human brain cells with viruses, but it is clearly a theoretical possibility and an interesting avenue to explore. Secondly, optogenetics is primarily a research tool – one that we hope will lead us to a greater understanding of brain circuit function and dysfunction, which, in turn, will allow us to develop new therapeutic approaches. When people like Karl Deisseroth talk about its relevance to psychiatric disease, this is what they mean: </span><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">“Despite the enormous efforts of clinicians and researchers, our limited insight into psychiatric disease (the worldwide-leading cause of years of life lost to death or disability) hinders the search for cures and contributes to stigmatization. Clearly, we need new answers in psychiatry.”</span><span lang="EN-GB"> As quoted and misrepresented <a href="http://blogs.scientificamerican.com/cross-check/2013/09/01/why-optogenetics-doesnt-light-me-up-the-sequel/">here</a>.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Finally, to end on a positive note, here are a few of my personal favourites from the recent literature where optogenetics approaches have generated real and novel insights into the organisation and function of specific brain circuits:</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/23817549"><span style="mso-ansi-language: EN-US; mso-bidi-font-family: &quot;Times New Roman&quot;; mso-bidi-font-weight: bold; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-font-kerning: 18.0pt;">Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons</span></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/23708967"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Distinct behavioural and network correlates of two interneuron types in prefrontal cortex</span></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/22367547"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Gain control by layer six in cortical circuits of vision</span></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/23515155"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Distinct extended amygdala circuits for divergent motivational states</span></a></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/23235832"><br /></a></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/23235832"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons</span></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/23064228"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Input-specific control of reward and aversion in the ventral tegmental area</span></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/21307935"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Functional identification of an aggression locus in the mouse hypothalamus</span></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/22801496"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Deconstruction of a neural circuit for hunger</span></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><a href="http://www.ncbi.nlm.nih.gov/pubmed/23888038"><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">Creating a false memory in the hippocampus</span></a></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2013/09/why-optogenetics-deserves-hype.htmlnoreply@blogger.com (Kevin Mitchell)15tag:blogger.com,1999:blog-6146376483374589779.post-6185372921349357642Tue, 02 Jul 2013 12:08:00 +00002013-07-02T05:08:50.228-07:00behavioural traitsepistasisepistaticgenetic interactionsgenetic predictionGWASmousequantitative traitsNo gene is an island<div dir="ltr" style="text-align: left;" trbidi="on"><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-6CQrrZ-Mf2o/UdK-hT00JNI/AAAAAAAAAc4/pnTME70cHjo/s288/Man+trapped+in+genome.jpg" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" src="http://4.bp.blogspot.com/-6CQrrZ-Mf2o/UdK-hT00JNI/AAAAAAAAAc4/pnTME70cHjo/s288/Man+trapped+in+genome.jpg" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><a href="http://www.ancestryreport.com/genetics-environmental-factors-and-the-sense-of-self/">Source</a></td></tr></tbody></table><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB; mso-fareast-language:JA;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB; mso-fareast-language:JA;} @page WordSection1 {size:595.0pt 842.0pt; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --></style> <br /><span lang="EN-GB">Many people, scientists and non-scientists alike, object to what they perceive as <a href="https://en.wikipedia.org/wiki/Genetic_determinism">genetic determinism</a>. This is often a reaction to geneticists apparently over-reaching and claiming that some trait or condition is “caused by” a single gene. A common rejoinder is that any biological process obviously involves many hundreds of gene products, interacting with each other in complex ways and so it is nonsense to say that the trait is determined by a single gene. That is absolutely true, if you are using the word “gene” purely in the molecular biology sense – as a piece of DNA that encodes a particular product (usually a protein). But geneticists also use it in the original sense, as a unit of heredity – a genetic variant or mutation that can be passed on across generations and that influences some phenotype.</span> <div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Genetics is not about how a characteristic arises, it is about how <i style="mso-bidi-font-style: normal;">variation</i> in that characteristic arises. For example, when you are describing someone, you might say: “She’s got blue eyes”, but you probably wouldn’t say: “She’s got two eyes”. Both characteristics are determined by the genetic program, but only one is affected by genetic variation. Eye colour is therefore a trait, because it varies across the population and that variation is due to genetic differences. Having blue eyes, insofar as it necessarily involves having eyes in the first place, is obviously not caused by a single piece of DNA – it takes thousands of gene products to build eyes, blue or otherwise. But having eyes that are blue, <i style="mso-bidi-font-style: normal;">as opposed to brown</i>, can be due to a single genetic variation.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">As it happens, though, eye colour is also a <a href="http://www.ncbi.nlm.nih.gov/pubmed/19619260">good example</a> of genetic interactions. Because, while it’s true that a single mutation can explain the difference in eye colour between some people, it’s also true that many people carry more than one such mutation in any of several different genes. The ultimate colour that emerges is thus often determined by interactions amongst multiple genetic variants. </span></div><div class="MsoNormal"><br /></div><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-QnVJI7ZDAXI/UdK-QGqMipI/AAAAAAAAAcw/AbdaRlqZNns/s1158/height+distribution-2.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="126" src="http://3.bp.blogspot.com/-QnVJI7ZDAXI/UdK-QGqMipI/AAAAAAAAAcw/AbdaRlqZNns/s400/height+distribution-2.jpg" width="400" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Distribution of heights in female and male college students (<a href="http://mindprod.com/jgloss/histogram.html">source</a>)</td></tr></tbody></table><div class="MsoNormal"><span lang="EN-GB">This is even more true for traits like height or IQ which differ in a <a href="http://en.wikipedia.org/wiki/Quantitative_trait_locus">quantitative</a> way across the population. The differences between any two individuals for traits like these are typically not caused by a single genetic variant, but by many. When we talk of genetic interactions, we are asking how the effects of such mutations combine. Do their effects simply sum up or do they interact in a more complex way? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This is an important question because it affects our ability to discover the contributing mutations in the first place and, crucially, to predict any particular individual’s phenotype from their genotype. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB"><a href="http://www.ncbi.nlm.nih.gov/pubmed/21429269">Height</a> provides a good example. <a href="http://en.wikipedia.org/wiki/Genome-wide_association_study">Genome-wide association studies</a> with huge numbers of people (both subjects and authors) have identified variable positions in the genome that show a statistical association with height. While the sequence at most positions in the genome is the same in most people in the world, around one in a thousand positions comes in different flavours – at <a href="http://en.wikipedia.org/wiki/Single_nucleotide_polymorphism">such positions</a>, the DNA might be an “A” in some people, but a “T” in others. By looking at millions of such sites, researchers have <a href="http://www.ncbi.nlm.nih.gov/pubmed/21429269">found 180</a> where the average height of people with one version, say the “T”, is very slightly greater than the average of those with the “A”. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For any individual, you can then count how many “tall” variants they have across all these sites. If you plot the distribution of this score across the population you can see how it correlates with height. It turns out this relationship is remarkably linear. As you increase the number of tall variants, the average height continues to increase at the same rate – people don’t suddenly start to get much more tall with each new variant and they also don’t reach a point where adding more tall variants starts to have a smaller effect. The exact same linear relationship is seen for genetic variants affecting <a href="http://en.wikipedia.org/wiki/Body-mass_index">body-mass index</a>.</span></div><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-UHNrArNvCZY/UdK6pnomq7I/AAAAAAAAAb4/pk7DeqAc_yQ/s417/BMI+histogram.jpg" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="236" src="http://4.bp.blogspot.com/-UHNrArNvCZY/UdK6pnomq7I/AAAAAAAAAb4/pk7DeqAc_yQ/s320/BMI+histogram.jpg" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span lang="EN-GB">From <a href="http://www.ncbi.nlm.nih.gov/pubmed/20935630">Speliotes et al</a>. (This graph is kind of misleading because it makes the relationship look very predictive by plotting a single value for mean height in each bin. For any particular number, there will still be a very wide range of heights – the average is just slightly different. This is similar to the effect of the Y chromosome – the average height of men is greater than the average height of women but if all you know about someone is their sex you have effectively no predictive power of their specific height). </span></td></tr></tbody></table><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">To me, this is a genuinely surprising result. It seems to go against expectations from experimental genetics, where non-linear (or “<a href="http://en.wikipedia.org/wiki/Epistatic">epistatic</a>”) interactions between mutations are the norm – ubiquitous really. It is quite common, for example, for two mutations, in two different genes, to have no effect singly but a drastic effect when combined. Or for a mutation to have very different effects on different genetic backgrounds (this is true for disease-causing mutations in humans as well as in animals). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">By contrast, the results from genome-wide association studies in humans seem to suggest that it is simply the number of such variants that matters in any individual and that the precise combination has little effect. Indeed, that is precisely how it has been interpreted by people who suggest that the value of such a score could be used to predict an individual’s phenotype. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The problem with such an interpretation is that genome-wide association studies give us only an average effect of each variant across the population – i.e., they measure the statistical effect of having one version of a particular variant versus another, averaging all other genetic variation out. Each such number is computed independently. If there are many variants involved and some of them show non-additive interactions, we would never see that because the number of individuals sharing both those particular variants is such a small percentage of our sample and the background of additional variants will be so diverse that any non-additive interactions will tend to average out. Indeed, it has <a href="http://www.ncbi.nlm.nih.gov/pubmed/18454194">been shown</a> that you can mathematically treat the interactions as additive across the population, whether they are or not in individuals – at least for the purposes of identifying variants affecting a trait.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">But that doesn’t mean they actually are additive and this remains a crucial question for our ability to extrapolate population averages to make predictions about individuals. The importance and ubiquity of such non-additive interactions is revealed by a powerful approach that is possible in animals.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">If we have two individual organisms that differ in some trait, presumably due to the effects of multiple genetic differences, then we can imagine a thought experiment: what would happen if we could decompose these mutations – if we could look at their effects one-by-one, to see how much each one contributes to the difference and to compare this with their combined effects?</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Obviously, that experiment is not possible with two individual organisms. But it is possible if we have <i style="mso-bidi-font-style: normal;">clones</i> of those individuals. Exactly that situation exists for lines of inbred mice.<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-skiToAv9Pj0/UdK78zgQxgI/AAAAAAAAAcI/86K5oA_lKUo/s500/mouse+clones.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="111" src="http://4.bp.blogspot.com/-skiToAv9Pj0/UdK78zgQxgI/AAAAAAAAAcI/86K5oA_lKUo/s200/mouse+clones.jpg" width="200" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><a href="http://futurescope.tumblr.com/post/47191141923/581-clones-from-one-mouse-from-singularityhub">Source</a></td></tr></tbody></table></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Many different lines (or strains) of lab mice exist, most of which are <a href="http://en.wikipedia.org/wiki/Inbred_strain">completely inbred</a>. That is, they have been backcrossed for so many generations that no genetic variation exists within the strain. Each animal within the strain is genetically identical – even the two copies that each animal possesses of each chromosome are genetically identical. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">When each such line was generated, some arbitrary spectrum of genetic variants was effectively frozen in place – while there is no genetic variation left in any particular line, there is lots of genetic variation between lines. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">This causes many phenotypic differences between them. These are most obvious in things like coat colour, but extend to all kinds of traits, including behavioural ones. Mice from some lines may be more active, more anxious, more sociable, more aggressive, more clever (in mouse terms, that is – the inbred ones are not the brightest at the best of times), or differ in many other behavioural tendencies. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now, if you’re a scientist interested in the genetics of behaviour, these lines are a gold mine. If you can figure out which of the genetic differences between two lines account for some behavioural difference, you would have an entry point into the biological processes controlling that behaviour (whether it’s aggression, anxiety or mouse-smarts). Trouble is, these differences are rarely simple. In fact, they can be complicated in very unexpected ways. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">First, differences in quantitative traits like behavioural tendencies rarely come down to a single genetic difference between strains. Crossing strains together (say a highly active and a less active strain) typically generates F1 hybrid offspring with a value for the trait that is somewhere between the two parental lines. By <a href="http://en.wikipedia.org/wiki/Backcrossing">backcrossing</a> these hybrids to either of the parental lines and correlating chromosome inheritance with the value of the trait, it is possible to map out regions of the genome influencing the trait (known as <a href="http://en.wikipedia.org/wiki/Quantitative_trait_loci">quantitative trait loci</a>). A typical finding is that there may be anywhere from 5 to 10 mappable loci contributing to the differences in the trait between the two lines. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now comes the unexpected part. Say you have mapped 10 loci that all seem to contribute to the difference between a high and a low activity strain. You might expect that each of these 10 different regions would contribute a small percentage to the phenotypic difference and that their effects would simply add up, quantitatively speaking. That is, if you had one locus that caused 10% of the increase in activity, and another that caused 15% of it, that if you combined both of them, you would see 25% of the increase. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">How could we test these expectations? What you would like to be able to do is examine the effects of each of these loci by themselves, rather than comparing the two strains with all 10 of those differences. Exactly that kind of experiment is made possible by the generation of <a href="http://www.ncbi.nlm.nih.gov/pubmed/17071995">chromosome substitution strains</a>. These are lines that have been generated by crossing together two strains (let’s call them A and B) and then backcrossing the hybrids to the A strain, while molecularly tracking inheritance of just one of the chromosomes from the B strain (and vice versa). Over time, this can generate a series of lines (one for each chromosome) that have the full genetic background of the A strain, with the exception of a single B-type chromosome. </span></div><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="http://1.bp.blogspot.com/-L70MmMSZcBI/UdK9ZeFN-QI/AAAAAAAAAcY/ZPEKrnzCdck/s720/Slide1.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="http://1.bp.blogspot.com/-L70MmMSZcBI/UdK9ZeFN-QI/AAAAAAAAAcY/ZPEKrnzCdck/s640/Slide1.jpg" width="640" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><a href="http://www.ncbi.nlm.nih.gov/pubmed/22064512">Source</a></td></tr></tbody></table><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Now you can ask exactly the question we wanted to ask – what is the effect on the trait of each of the individual loci in isolation? If we start with the background of the low activity A strain, and look at lines that each have one B chromosome containing a “high activity” allele, where will their phenotypes lie on the line between the parental strains? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Well, here’s the surprise. In many cases (like <a href="http://www.biomedcentral.com/1471-2156/13/38">here</a> and <a href="http://www.pnas.org/content/105/50/19910.long">here</a>), the phenotypic effects of these single loci are much bigger than you would expect – often explaining 50% or more of the difference between the two strains. This means that if you simply added up their effects you would get much more than the 100% of the difference you started with. In fact, the range for behavioural traits averages at ~800%, if you simply add up the effects of the decomposed individual loci. Even more remarkably, some of the individual chromosome substitution strains show a phenotypic level that is outside the range of either of the initial parents, sometimes even moving the trait distribution in the opposite direction to the “donor” parent strain. </span></div><div class="MsoNormal"><br /></div><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-QFY_Z0wUCYE/UdK9rtJ7isI/AAAAAAAAAcg/Maz5HAkhzrw/s1065/Table+from+Spiezio.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="113" src="http://4.bp.blogspot.com/-QFY_Z0wUCYE/UdK9rtJ7isI/AAAAAAAAAcg/Maz5HAkhzrw/s640/Table+from+Spiezio.jpg" width="640" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><a href="http://www.biomedcentral.com/1471-2156/13/38">Spiezio et al</a></td></tr></tbody></table><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">&nbsp;<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-vtHceezAY4c/UdK-BCw7_dI/AAAAAAAAAco/wJ3TOk4lHJU/s528/Table+4+from+Spiezio.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="260" src="http://4.bp.blogspot.com/-vtHceezAY4c/UdK-BCw7_dI/AAAAAAAAAco/wJ3TOk4lHJU/s400/Table+4+from+Spiezio.jpg" width="400" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><a href="http://www.biomedcentral.com/1471-2156/13/38">Spiezio et al</a></td></tr></tbody></table></span></div><div class="MsoNormal"><span lang="EN-GB">These results clearly show that non-additive interactions for variants affecting quantitative traits are common, large and unpredictable. They are a ubiquitous feature of the genetic architecture of quantitative traits, whether morphological, physiological or behavioural and are seen across many different species, including <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=23086219">worms</a>, <a href="http://www.pnas.org/content/109/39/15553.long">flies</a>, <a href="http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002180">chickens</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/23376951">yeast</a>. Even if such interactions average out across all the combinations encountered in the population, so that they appear additive, statistically, this biological reality places a severe limit on our ability to predict any individual’s phenotype based purely on additive calculations. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In fact, even if we can begin to define some non-additive interactions by studying the phenotypic effects of various pairwise combinations across many people, it will still be very difficult to predict any new individual’s phenotype because, just like each of the distinct chromosome substitution strains in mice, their precise combination of all variants will never have been seen before. In a strange way, I find that comforting – we are each much more unique than a purely statistical overview would suggest. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB"><br /></span></div><div class="MsoNormal"><br /></div></div>http://www.wiringthebrain.com/2013/07/no-gene-is-island.htmlnoreply@blogger.com (Kevin Mitchell)18tag:blogger.com,1999:blog-6146376483374589779.post-8216798866158847516Mon, 13 May 2013 11:41:00 +00002013-05-20T00:00:51.142-07:00eugenicsgenetic architecturegeneticsintelligencepredictionselectionThe New Eugenics – same as the Old Eugenics?<div dir="ltr" style="text-align: left;" trbidi="on"><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB; mso-fareast-language:JA;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; mso-themecolor:hyperlink; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB; mso-fareast-language:JA;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style><span lang="EN-GB">Did I miss a memo? Has eugenics somehow become respectable again? </span><br /><div class="MsoNormal"><br /></div><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-zSWZMhO940s/UZDOGIIPXiI/AAAAAAAAAbA/AYgJ_SQO4fg/s1600/designer+baby+einstein.jpg" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="200" src="http://3.bp.blogspot.com/-zSWZMhO940s/UZDOGIIPXiI/AAAAAAAAAbA/AYgJ_SQO4fg/s200/designer+baby+einstein.jpg" width="194" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><a href="http://indiatoday.intoday.in/story/technology-will-govern-future-of-indian-medical-services/1/180092.html">Source</a></td></tr></tbody></table><div class="MsoNormal"><span lang="EN-GB">There has been a lot of talk lately, in the blogosphere at least (<a href="http://www.vice.com/read/chinas-taking-over-the-world-with-a-massive-genetic-engineering-program">1</a>, <a href="http://edge.org/responses/q2013">2</a>, <a href="http://westhunt.wordpress.com/2012/03/09/get-smart/">3</a>, <a href="http://online.wsj.com/article/SB10001424127887324162304578303992108696034.html">4</a>, <a href="http://www.policymic.com/articles/30111/chinese-labs-are-engineering-genius-babies-should-the-u-s-follow-suit">5</a>), about the idea of using molecular genetics to predict and select for higher intelligence in humans (through <a href="http://en.wikipedia.org/wiki/Preimplantation_genetic_diagnosis">pre-implantation screening</a> of embryos, for example). The prevailing view among many discussing this idea seems to be that if we can do it, we obviously should do it. The casualness with which this conclusion is reached is astonishing to me, given the <a href="http://en.wikipedia.org/wiki/History_of_eugenics">history</a>of humanity’s efforts in this area. To many commentators, it seems to be a given that having more intelligent people, across the population, is not only obviously a good thing, but one that supersedes any other considerations. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Selecting for increased intelligence doesn’t sound so bad, when you phrase it like that, until you realise that it actually involves the converse – selecting against individuals with lower predicted intelligence. I am not ascribing the following chain of thought to any particular persons, but here is the fundamental logic of eugenics, applied to intelligence:</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">For any individual, being more intelligent is better than being less intelligent. (All else being equal, that’s fair enough, I suppose). People who are more intelligent are therefore better than people who are less intelligent. (See how easy it is to get there?) At least, it would be good if we had more of the former and less of the latter. We should, as a society, seek ways to ensure that is the case. In the past, this would have involved policies on who is allowed to live or breed or migrate into a society, or inducements to get the more clever people to breed like they vote in Chicago – early and often. Nowadays, if we can employ pre-implantation genetic screening to predict intelligence, then we should use that method, or at least make it available, to select and implant those embryos that are predicted to be more intelligent. This will inevitably be at the expense of ones predicted to be less intelligent. The former should be granted life and the latter should not. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Is all that just self-evident? Is that how we should define progress in our society? </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The amazing thing, in the pieces I have been reading recently, is that something approaching this position seems to have been reached not after lengthy and sober consideration of the moral and ethical issues surrounding the idea, but in total disregard for them. The following questions don’t seem to have come up: Is it right to claim some people are superior to others or of “<a href="http://edge.org/responses/q2013">higher quality</a>”? Is it right to actively select between embryos (or to selectively abort foetuses) on any criterion? (Many people would say no, though it <a href="http://www.wiringthebrain.com/2012/05/gattaca-and-coming-future-of-genetic.html">already happens</a> routinely for serious medical conditions, and even for sex in many parts of the world). If there are some criteria that can be considered legitimate, what are they? How do we decide? Who makes those decisions? Should society as a whole ever have the right to dictate such decisions? Or should society allow complete freedom to individuals to make such decisions on any criteria they wish? If selection is permissible, is intelligence really the primary trait on which such selection should be based? What about kindness or decency or bravery or empathy or not being a douche? Do any of those get a look in? Would we lose anything from human society by selecting purely for those who perform better on IQ tests?</span></div><div style="text-align: left;"></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The impression one gets is that the people proposing such ideas think the world would be a better place if there were more people like them in it. The spectacle of cosseted academics bemoaning the degraded intellect of the masses and suggested something should be done about it is not an appealing one. And it is not without consequences.</span></div><div class="MsoNormal"><br /></div><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: right; margin-left: 1em; text-align: right;"><tbody><tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-ra2JfHdOAQc/UZDPNdzOFFI/AAAAAAAAAbY/9mCsCeO3GTE/s1600/eugenics-sign.jpg" imageanchor="1" style="clear: right; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="210" src="http://3.bp.blogspot.com/-ra2JfHdOAQc/UZDPNdzOFFI/AAAAAAAAAbY/9mCsCeO3GTE/s320/eugenics-sign.jpg" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB; mso-fareast-language:JA;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; mso-themecolor:hyperlink; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB; mso-fareast-language:JA;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style> </td></tr></tbody></table><div class="MsoNormal"><span lang="EN-GB">There seems to be little recognition of the potential harm to the reputation of genetics as a science when it is <a href="http://usatoday30.usatoday.com/tech/science/columnist/vergano/2011-04-22-eugenics-journal_N.htm">associated</a>with public claims of this sort. This discipline still bears the taint of previous misuses, most notably as justification for the murderous <a href="http://en.wikipedia.org/wiki/Nazi_eugenics">eugenic policies of Nazi Germany</a> or enforced sterilisations of the “feeble-minded” in many <a href="http://en.wikipedia.org/wiki/Eugenics_in_the_United_States">US states</a>which ran from the early 1900’s to as late as 1977 in North Carolina. Many other countries enacted <a href="http://en.wikipedia.org/wiki/History_of_eugenics">similar policies</a>. </span></div><div class="MsoNormal"><br /></div><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-J75KMzXlCiE/UZDO2Njnr7I/AAAAAAAAAbQ/xxnkdu2cSIQ/s1600/Prof+X.jpg" imageanchor="1" style="clear: right; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="200" src="http://3.bp.blogspot.com/-J75KMzXlCiE/UZDO2Njnr7I/AAAAAAAAAbQ/xxnkdu2cSIQ/s200/Prof+X.jpg" width="150" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><a href="http://lisavoisin.wordpress.com/2012/04/27/x-man-three-quick-and-interesting-facts-about-the-charles-xavier/">Source</a></td></tr></tbody></table><div class="MsoNormal"><span lang="EN-GB">The themes of genetic classism and discrimination and of elitist scientists “playing God” resonate widely in our culture (from Shelley’s <a href="http://en.wikipedia.org/wiki/Frankenstein">Frankenstein</a>to <a href="http://en.wikipedia.org/wiki/Gattaca">GATTACA</a> to the <a href="http://en.wikipedia.org/wiki/X-men">X-Men</a>). Indeed, the extensive <a href="http://online.wsj.com/article/SB10001424127887324162304578303992108696034.html?mod=WSJ_LifeStyle_Lifestyle_5">coverage</a>of a study on the genetics of IQ that is currently underway at the Beijing Genomics Institute (<a href="http://www.genomics.cn/en/index">BGI</a>) suggests that the media knows a good story when it sees it. It seems to me that this has attracted attention not because of any scientific advance or discovery (the study has not yet been completed) but because of the way those involved and commenting on it have acted as cheerleaders for the idea of prenatal prediction and selection. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Here’s Prof. Geoffrey Miller (of NYU), in an interview for an article egregiously entitled “<a href="http://www.vice.com/read/chinas-taking-over-the-world-with-a-massive-genetic-engineering-program">China is engineering genius babies</a>” on vice.com (whatever that is): </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal" style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .25in; margin-right: 28.0pt; margin-top: 0in;"><span lang="EN-GB">“</span><b><span lang="EN-GB" style="font-family: Cambria; mso-ascii-theme-font: minor-latin; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-hansi-theme-font: minor-latin;">How does Western research in genetics compare to China’s?</span></b><b><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;"><br /></span></b><span lang="EN-GB" style="mso-bidi-font-family: &quot;Times New Roman&quot;; mso-fareast-font-family: &quot;Times New Roman&quot;;">We’re pretty far behind. We have the same technical capabilities, the same statistical capabilities to analyze the data, but they’re collecting the data on a much larger scale and seem to be capable of transforming the scientific findings into government policy and consumer genetic testing much more easily than we are. Technically and scientifically we could be doing this, but we’re not.”</span><span lang="EN-GB"></span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Some would argue it is not the place of scientists to decide the ethical issues – it is our job just to do the science. If society abuses it, well, that is not our fault. This is a case where I strongly disagree – we cannot disentangle the moral issues from the scientific ones. It is too easy to use scientific findings to justify policies that would otherwise be deemed abhorrent; too easy, <a href="http://en.wikipedia.org/wiki/Is%E2%80%93ought_problem">as Hume noted</a>, to mistakenly derive a prescription of how things <i style="mso-bidi-font-style: normal;">ought</i> to be from a description of how they <i style="mso-bidi-font-style: normal;">are</i>.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In this case the science is too complex and our understanding still far too fragmentary to even describe how things are. But reading some of the commentaries one would think that our ability to predict intelligence based on molecular genetics is really just around the corner; that we will have this knowledge in hand within a few years and Pandora’s box will have been opened, whether we like it or not. I find this scenario highly implausible, for several reasons. </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">First, we have not yet identified any genes “for intelligence”. We know many that, when mutated, can cause intellectual disability (<a href="http://www.ncbi.nlm.nih.gov/pubmed/21910631">many hundreds</a>, in fact), but none that clearly contribute to variation in the normal range (normal in the statistical sense of that word). Zero, zip, bupkis. We are starting from effectively complete ignorance as of this moment. In fact, we don’t even understand the <a href="http://www.wiringthebrain.com/2012/07/genetics-of-stupidity.html">genetic architecture of intelligence</a>. It is clearly very highly heritable, but we don’t know how many genes are involved, either across the population or in any individual, we don’t know whether the genetic variants are common or rare, we don’t know whether they specifically affect intelligence or have more general effects on robustness of the genetic program and its execution to build an efficient brain and we don’t know how multiple such variants would interact with each other. That’s a lot of don’t knows.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">The answers to those questions will determine the best strategies for finding variants that affect intelligence and also, crucially, our ability to predict an <i style="mso-bidi-font-style: normal;">individual’s</i>IQ based on signatures that we can only detect by averaging across the population. If we want to be fanciful, we can imagine a future scenario where we have in fact identified many genetic variants across the population that clearly contribute to differences in intelligence. Some may be common, but my expectation is that most would be quite rare. Now we want to look at some new individual’s DNA and predict their IQ based on that knowledge (or maybe look at two individuals and predict which one’s IQ will be higher, even if we can’t put a number on it). </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">Here are the problems: first, IQ is indeed highly heritable, but a lot of the variation across the population is non-genetic (at least 20-30%); that imposes a significant limit on accuracy of even a perfect genetic predictor. Second, if IQ is largely affected by rare mutations, then each new person will have some IQ-affecting variants that we have never seen before in our population sample and that we will be unable to recognise as such. Third, any individual will also have a unique, never-before-seen combination of variants, which may interact in highly unexpected ways. Finally, any such predictor would have to be extremely precise to distinguish between the IQ of not just any two random individuals, but two siblings, where the range will obviously be much narrower.</span></div><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">To paraphrase Yogi Berra, making predictions is hard, especially about the future. But I am willing to go out on a very sturdy limb and predict that we will not be able to build useful predictors for IQ any time soon. We’re not there, we’re not nearly there and there may even be fundamental limits that mean we will never get there.</span></div><div class="MsoNormal"><br /></div><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-8BINIoGglGI/UZDPx7XKfrI/AAAAAAAAAbg/4oSHOm9Rc1c/s1600/germline+modification.jpg" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="320" src="http://3.bp.blogspot.com/-8BINIoGglGI/UZDPx7XKfrI/AAAAAAAAAbg/4oSHOm9Rc1c/s320/germline+modification.jpg" width="247" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span id="goog_76828095"></span><a href="http://www.blogger.com/"><span id="goog_76828086"></span> <style><!-- /* Font Definitions */ @font-face {font-family:"ＭＳ 明朝"; mso-font-charset:78; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB; mso-fareast-language:JA;} a:link, span.MsoHyperlink {mso-style-priority:99; color:blue; mso-themecolor:hyperlink; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; mso-style-priority:99; color:purple; mso-themecolor:followedhyperlink; text-decoration:underline; text-underline:single;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-ansi-language:EN-GB; mso-fareast-language:JA;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} </style>&nbsp;</a></td></tr></tbody></table><span lang="EN-GB">A <a href="http://westhunt.wordpress.com/2012/03/09/get-smart/">post from 2012</a>by Greg Cochran goes even further, suggesting that a variety of approaches to improve intelligence are imminent, from selection to molecular interventions designed to correct mutations lowering intelligence. This not only fails to consider any of the ethical and moral issues described above, it similarly ignores the additional ones that arise when considering modifying the human germline! It also greatly exaggerates our technical abilities to do that. Yes, we can modify the germline in model organisms like mice, but what this simple statement glosses over is the fact that generating any such genetically modified individual involves a lot of trial and error. This science is messy. Most of the embryos (or cells) one tries to modify do not get modified in the expected way and one has to screen through many hundreds typically to get ones with the desired change. (Even those can sometimes have other, random changes one didn’t plan for). This is clearly not a strategy we could countenance in humans.</span><br /><div class="MsoNormal"><br /></div><div class="MsoNormal"><span lang="EN-GB">In the meantime, before we go proposing scientifically impractical and morally questionable extreme measures, we have a proven and powerful tool to make people smarter: education. </span></div><div class="MsoNormal"><br /><br /></div></div>http://www.wiringthebrain.com/2013/05/the-new-eugenics-same-as-old-eugenics.htmlnoreply@blogger.com (Kevin Mitchell)56tag:blogger.com,1999:blog-6146376483374589779.post-167450564524197501Thu, 21 Mar 2013 13:29:00 +00002013-03-21T06:29:31.471-07:00chancedevelopmental trajectoriesemergenceepilepsygenotype-phenotype mappingpsychosisschizophreniaThe genetics of emergent phenotypes <div dir="ltr" style="text-align: left;" trbidi="on"> <style><!-- /* Font Definitions */ @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:Cambria; mso-fareast-theme-font:minor-latin; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} a:link, span.MsoHyperlink {mso-style-noshow:yes; color:blue; text-decoration:underline; text-underline:single;} a:visited, span.MsoHyperlinkFollowed {mso-style-noshow:yes; color:purple; text-decoration:underline; text-underline:single;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --></style> <br /><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://1.bp.blogspot.com/-5Oy2Bv6hw3Y/UUsKuGbceOI/AAAAAAAAAak/UGpSBd4aTeU/s1600/brain+disorders+art.png" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img alt="http://www.socialsciences.leiden.edu/psychology/organisation/chn/neuro/education/master.html" border="0" src="http://1.bp.blogspot.com/-5Oy2Bv6hw3Y/UUsKuGbceOI/AAAAAAAAAak/UGpSBd4aTeU/s1600/brain+disorders+art.png" title="" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><a href="http://www.socialsciences.leiden.edu/psychology/organisation/chn/neuro/education/master.html">Source</a></td></tr></tbody></table><div class="MsoNormal">Why are some brain disorders so common? Schizophrenia, autism and epilepsy each affect about 1% of the world’s population, over their lifetimes. Why are the specific phenotypes associated with those conditions so frequent? More generally, why do particular phenotypes exist at all? What constrains or determines the types of phenotypes we observe, out of all the variations we could conceive of? Why does a system like the brain fail in particular ways when the genetic program is messed with? Here, I consider how the difference between “concrete” and “emergent” properties of the brain may provide an explanation, or at least a useful conceptual framework </div><div class="MsoNormal"><br /></div><div class="MsoNormal">There is now <a href="http://www.ncbi.nlm.nih.gov/pubmed/20832285">compelling evidence</a> that disorders like epilepsy, schizophrenia and autism can be caused by mutations in any of a very large number of different genes (sometimes singly, sometimes in combinations). This is fundamentally changing the way we think about these disorders. It is no longer tenable to consider them as unitary categories. Instead, it is very clear that the underlying etiology is extremely heterogeneous – possibly more so than for any other human disease.</div><div class="MsoNormal"><br /></div><div class="MsoNormal">How can this fact be explained? Why is it that mutations in so many different genes (perhaps thousands) can give rise to the specific phenotypes associated with those disorders? </div><div class="MsoNormal"><br /></div><div class="MsoNormal">The normal logic of genetic analysis entails some correspondence between the phenotypes associated with mutations in specific genes and the functions of the products encoded by those genes. This connection between mutation and phenotype is one of the main reasons why experimental genetics is so powerful. For example, if we carry out a genetic screen for mutations affecting cell death in a worm, or embryonic patterning in a fruit fly, the expectation is that the genes we discover will be directly involved in those processes. That is how the molecular processes regulating cell death and embryonic patterning were discovered. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">This logic can sometimes be applied to humans too – but not always. Let’s consider two genetic conditions – microcephaly and epilepsy – both affecting the brain, but in quite distinct ways. </div><div class="MsoNormal"><br /></div><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-05rETI05qxQ/UUsISvaxfsI/AAAAAAAAAaU/peByPW-l7yg/s1600/microcephaly+MRI.png" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="200" src="http://4.bp.blogspot.com/-05rETI05qxQ/UUsISvaxfsI/AAAAAAAAAaU/peByPW-l7yg/s200/microcephaly+MRI.png" width="155" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">MRI of child with microcephaly (top). <a href="http://archives.focus.hms.harvard.edu/2002/Oct25_2002/research_briefs.html">Source</a>.</td></tr></tbody></table><div class="MsoNormal"><a href="http://en.wikipedia.org/wiki/Microcephaly">Microcephaly</a>is a rare condition characterised by a small brain. In particular, the cerebral cortex is smaller than normal, due to a defect in the generation of the normal number of neurons in this brain area. It can be inherited in a simple, Mendelian fashion, due to a mutation in any one of <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=19850369">at least six different genes</a>. Remarkably, the proteins encoded by these genes are all involved in some aspect of cell division of neuronal progenitors. In particular, they determine whether early divisions expand the initial pool of progenitors (in the normal situation) or prematurely generate neurons (when any of these genes is mutated).<span style="mso-spacerun: yes;">&nbsp; </span></div><div class="MsoNormal"><br /></div><div class="MsoNormal">The genes implicated in microcephaly are thus directly involved in the process affected: the generation of neurons in the cerebral cortex. It is not too inaccurate to say that that is what these genes are “for”. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">This is not the case for epilepsy. It too can be inherited due to specific mutations, but there are many, many more of them and the known genes involved have <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=21277190">diverse functions</a>: from controlling cell migration or specifying synaptic connectivity to encoding ion channels or metabolic enzymes. These are not genes “for” regulating the spatial and temporal dynamics of electrical activity in neuronal networks. </div><div class="MsoNormal"><br /></div><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://1.bp.blogspot.com/-v0DQq_5w-v8/UUsJ2fmN84I/AAAAAAAAAac/K5WObVJAn-k/s1600/epileptic+brain.png" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="138" src="http://1.bp.blogspot.com/-v0DQq_5w-v8/UUsJ2fmN84I/AAAAAAAAAac/K5WObVJAn-k/s200/epileptic+brain.png" width="200" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><a href="http://mindblog.dericbownds.net/2007/03/fascinating-rhythm.html">Source</a></td></tr></tbody></table><div class="MsoNormal">Put another way, the reason that we see microcephaly as a phenotype is that there are genes that control the process we are looking at – generation of neurons in the cortex. The existence of that phenotype thus reflects a property of the genetic system. In contrast, the generation of seizures does not relate in any meaningful way to the genetic system – instead, it is an emergent property of the neural system. We see that phenotype not because there are many genes directly controlling that process, but because it is a state that the brain tends to get into, in response to a wide diversity of insults. (Indeed, seizures are one of the symptoms sometimes associated with microcephaly).</div><div class="MsoNormal"><br /></div><div class="MsoNormal">I have used the term “emergent” twice now without defining it and had better do so before I get pilloried by those allergic to the word. There is good reason for a negative reaction, as the term is fraught with multiple meanings and seemingly mystical connotations. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">Concepts of emergence range from the mundane (the whole is more than the sum of its parts) to the magical (where the behaviour of a system is not reducible to or predictable from the state and interactions of all its components, and where new properties emerge apparently “for free”). In fact, it is possible to allow for new principles and properties at higher levels without invoking such mystical concepts or over-riding the fundamental laws of physics.</div><div class="MsoNormal"><br /></div><div class="MsoNormal">Nature is organised hierarchically into systems at different levels. Subatomic particles are arranged as atoms, atoms into molecules, molecules in cells, cells into tissues and organs, and ultimately organisms, individual organisms in collectives and societies. At each level, qualitatively novel properties arise from the collective action of the components at the level below. Emergence refers to the idea that many of these properties are highly unexpected and extremely difficult to predict (though not necessarily impossible in principle). One objection to the term is that it is therefore essentially a statement about us (about our level of understanding) and not about the system itself. I think it goes further than that, however, and does denote some principles of nature that actually exist in the world, regardless of whether we understand them or not.</div><div class="MsoNormal"><br /></div><div class="MsoNormal">While the emergent behaviour of a system is reducible to the microstates of the components at the level below and the fundamental physical laws controlling them, the emergent properties are not <i style="mso-bidi-font-style: normal;">deducible</i> purely from those laws. To put it another way, the microstates of a system are sufficient to explain the properties or macrostates observed at any moment but are not sufficient to answer another question – <a href="http://complexsystems.org/publications/pdf/emergence3.pdf">why those properties exist</a>. Why is it that those are the properties observed in that particular system, or that tend to be observed across diverse systems? These properties arise because additional laws or principles apply at the higher level, which constrain the arrangements of the components at the lower level <i style="mso-bidi-font-style: normal;">to some purpose</i>. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">Many of these principles of functional organisation are abstract and apply to diverse systems – principles of <a href="http://en.wikipedia.org/wiki/Network_theory">network</a> organisation, <a href="http://en.wikipedia.org/wiki/Cybernetics">cybernetics</a> and control theory, <a href="http://en.wikipedia.org/wiki/Information_theory">information</a>content, storage and processing, and many others. All of these principles constrain the architecture of a system in a way that ensures its optimality for some function. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">In artificial design of complex machines, these engineering principles are incorporated to ensure that the parts are arranged so as to produce the desired functions of the system as a whole. In living organisms, it is natural selection that does this work, leading to the illusion of design (or <a href="http://en.wikipedia.org/wiki/Teleonomy">teleonomy</a>), apparent only in hindsight. System architectures that produce useful emergent properties at the higher level (i.e., the phenotype of the organism, which is all that selection can see) are retained and those that do not are removed. In this way, the abstract engineering principles constrain the functional organisation of the components of the system – there are only certain types of arrangements that can generate specific functions. This is top-down causation, but over a vastly different timescale from the mystical, moment-to-moment versions proposed by some emergence theorists. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">Let’s move from the abstract to a more specific example and think about how these issues relate to the kinds of phenotypes we see when a system is challenged. Consider a complicated, highly specified system like a fighter jet. It has many different parts – engines, turbines, fuselage, flaps, wheels, weapons, etc. – each with multiple subcomponents and each with a specific job to do. If we were examining multiple designs for a jet, we might consider various specs for, say, the turbines. We might vary the number of blades, their size, angle, etc. These are all concrete properties of the system and there are a finite number of them. </div><div class="MsoNormal"><br /></div><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-Ax-f-B5sHrE/UUsFy_w61II/AAAAAAAAAZ8/HkPaPKeuFGw/s1600/emergent+properties.png" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="277" src="http://3.bp.blogspot.com/-Ax-f-B5sHrE/UUsFy_w61II/AAAAAAAAAZ8/HkPaPKeuFGw/s320/emergent+properties.png" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Source: <style><!-- /* Font Definitions */ @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:Cambria; mso-fareast-theme-font:minor-latin; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --></style><a href="http://www.edc.ncl.ac.uk/research/recentgraphic01.php/">Newcastle University</a> </td></tr></tbody></table><div class="MsoNormal">Contrast that with an emergent property of the jet, something like aerodynamic stability, fuel efficiency or even something harder to define, like “performance”. These properties depend on the specs of all the individual components of the plane, but also, more importantly, on their functional organisation and the interactions between them (and the interactions of the whole system with the environment). A property like performance is not easily linked to any specific component – instead it emerges in a highly non-linear fashion from the specs of all of the components of the system and how they are combined. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">If you randomly broke one component in the jet, it is thus much more likely that you would affect performance than that you would affect the turbines specifically. The bits of the turbines are not “for performance”, per se – they are for whatever job they do in the turbine. There aren’t any bits of the jet that you would say are “for performance”, in fact, but all of them can affect performance. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">The kinds of functions affected by disorders like epilepsy, autism or schizophrenia are like performance. For epilepsy, it is the highest-order properties of neural systems – the temporal and spatial dynamics of electrical activity. For schizophrenia and autism, it is functions like perception, cognition, sense of self, executive planning, social cognition and orderly thought – the most sophisticated and integrative functions of the human mind. These rely on the intact functioning of neural microcircuits in many different areas and the coordinated actions of distributed brain systems. Evolution has crafted a complex and powerful machine with remarkable capabilities, but those capabilities are consequently vulnerable to attack on any of a very large number of components. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">Thinking about these phenotypes in this way thus provides an explanation for why epilepsy and schizophrenia are so much more common than microcephaly. The mutational target – the number of genes in which mutations can cause a particular phenotype – is much, much bigger. (This obviates the need to invoke some kind of counter-balancing benefit of the mutations that cause these disorders to explain why they persist at a high frequency. The individual causal mutations do <i style="mso-bidi-font-style: normal;">not</i>persist – they are strongly selected against, but new mutations arise all the time. Under this <a href="http://en.wikipedia.org/wiki/Mutation%E2%80%93selection_balance">mutation-selection balance</a> model, the prevalence of a disorder is determined by an equilibrium between the mutational target size and the strength of selection). </div><div class="MsoNormal"><br /></div><div class="MsoNormal">But this perspective does not explain everything that needs explaining. These conditions do not manifest simply as a general decrease in brain “performance”. It is not just that normal brain functions are somewhat degraded. Instead, qualitatively new states or phenotypes emerge. <a href="http://en.wikipedia.org/wiki/Psychosis">Psychosis</a> is probably the most striking example – psychiatrists call the hallucinations and delusions that characterise psychosis “positive symptoms”, reflecting the fact that they are a novel, additional manifestation, not just a decrease in the function of specific mental faculties (as with the negative symptoms, such as a decrease in working memory).</div><div class="MsoNormal"><br /></div><div class="MsoNormal">Why does this specific, qualitatively novel state arise as a consequence of so many distinct mutations? This is where our fighter jet runs out of steam, as a (now mixed) metaphor. The problem with that metaphor is that fighter jets are designed and built from a blueprint. Parts of the blueprint correspond to parts of the jet and their arrangement is also specified directly on the blueprint. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">This is not at all the case for the anatomy of the brain. The genome is not a blueprint – there are no parts of the DNA sequence that correspond to parts of the brain. Instead, the structure of the brain emerges through <a href="http://en.wikipedia.org/wiki/Epigenesis_%28biology%29">epigenesis</a> – the execution of the developmental algorithms encoded in the genome, which direct the unfolding of the organism. (Aristotle coined this term epigenesis, which contrasted with the prevailing theory, known as pre-formationism – the idea that the fertilised egg already contains within it a teeny-weeny person, with all its bits in place, which simply grows over the period of gestation).</div><div class="MsoNormal"><br /></div><div class="MsoNormal">The ultimate phenotype of an organism is thus emergent in the more common sense of that word – it is something that arises over time. This emphasises the need to consider developmental trajectories when trying to understand the highly heterogeneous etiology of these disorders. </div><div class="MsoNormal"><br /></div><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody><tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-FWYAZ-Qq7vo/UUsGUWJpCoI/AAAAAAAAAaE/PpNXa6IWnEU/s1600/attractor+states.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="230" src="http://4.bp.blogspot.com/-FWYAZ-Qq7vo/UUsGUWJpCoI/AAAAAAAAAaE/PpNXa6IWnEU/s320/attractor+states.jpg" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Modified from: <a href="http://www-users.york.ac.uk/~lsdc1/SysBiol/kitano.robustness.naturegenetics.2004.pdf">Kitano, 2004</a></td></tr></tbody></table><div class="MsoNormal">Complex, dynamic systems tend to gravitate towards certain stable patterns of activity and interactions in the network. Such patterns are called “basins of attraction” or “<a href="http://en.wikipedia.org/wiki/Attractor">attractors</a>”, for short. You can think about them like hollows in a flat sheet, with the current network state represented by the position of a ball rolling over this landscape. The flat bits of this landscape represent unstable, fluid states that are likely to change. The hollows represent more stable states – particular patterns of activity of the network that are easy to get into and hard to get out of. Generally speaking, the deepest such basin will represent the typical pattern of brain physiology. It takes a big push to get the ball up and out of this basin. But there are other basins – alternative stable states and the pathophysiological state we recognise as psychosis may be one of those. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">Such alternate states may exist as by-products of the functional organisation of the system. The system architecture will have been selected to <a href="http://www-users.york.ac.uk/~lsdc1/SysBiol/kitano.robustness.naturegenetics.2004.pdf">robustly generate</a> a particular functional outcome. However, when individual components are interfered with, new functional states may emerge – ones that are unexpected and that the system has not been selected to produce. They arise instead as an emergent property of the broken system, as a specific failure mode. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">It is vital to understand not just the nature of such states, but the trajectories that dynamic systems (in this case organisms) follow to get into them. (In dynamic systems, the relations between components of the system are not fixed but change over time). If we take our flat sheet and tilt it from one end, turning it into a board with channels in it, rather than hollows, then we can represent the path of a developing organism through phenotype space, over time.&nbsp;</div><div class="MsoNormal"><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="http://3.bp.blogspot.com/-HvNsUmirK7Y/UUsGwO7heEI/AAAAAAAAAaM/RXLjZBTZAaQ/s1600/epigenetic+landscape.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" height="212" src="http://3.bp.blogspot.com/-HvNsUmirK7Y/UUsGwO7heEI/AAAAAAAAAaM/RXLjZBTZAaQ/s320/epigenetic+landscape.jpg" width="320" /></a></div><div class="MsoNormal">This is Conrad Waddington’s famous “<a href="http://en.wikipedia.org/wiki/Epigenetic_landscape">epigenetic landscape</a>” – a powerful metaphor for understanding how dynamic systems can be channelled into specific, stable states. The shape of the landscape will be determined by an individual’s genotype – some people may have much deeper channels heading towards typical brain physiology while others may have a greater chance of heading towards particular pathophysiological states, like psychosis or epilepsy. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">One reason why psychosis and epilepsy may be common states is that they can reinforce themselves, through altering the relations of components of the system. In a process known as “<a href="http://en.wikipedia.org/wiki/Kindling_model">kindling</a>”, seizures induce <a href="http://www.ncbi.nlm.nih.gov/pubmed/20944823">changes in neuronal networks</a> that render them increasingly excitable and more likely to undergo further seizures. A <a href="http://www.wiringthebrain.com/2012/10/its-not-crime-its-cover-up-reactivity_12.html">similar dynamic process</a>, involving homeostatic processes in dopaminergic signaling pathways, may be involved in psychosis. These homeostatic mechanisms in the developing brain can, under certain circumstances, be maladaptive, pushing the network state into a particular pathophysiological pattern, in response to diverse primary insults. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">Finally, a developmental perspective can also provide an explanation for the high levels of phenotypic variability observed with mutations conferring risk for psychiatric disorders. Such mutations can manifest in different ways, statistically increasing risk for multiple conditions. A person’s risk for developing schizophrenia is statistically much higher if they have a close relative with the condition, but their risks of developing autism or epilepsy (or bipolar disorder or depression or attention-deficit hyperactivity disorder) are all also higher. Even monozygotic (“identical”) twins are often not concordant for these clinical diagnoses. So, while genetics can lead to a much greater susceptibility to these conditions, whether a specific individual actually develops them depends also on other factors. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">One of those factors, often overlooked, is <a href="http://www.wiringthebrain.com/2009/06/nature-nurture-and-noise.html">intrinsic developmental variation</a>. The development of the brain is inherently <a href="http://www.wiringthebrain.com/2012/06/probabilistic-inheritance-and.html">probabilistic</a>, not deterministic (more like a recipe than a blueprint). This is evident at the level of individual cells, nerve fibres and synapses and can manifest at the macro level as variation in specific traits or symptoms in individuals with the exact same genotype. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">Waddington’s landscape can also visualise this important role of chance in determining an individual’s eventual phenotypic outcome. If you roll a marble down this board multiple times, you will get multiple outcomes, essentially by chance (due to thermodynamic noise at the molecular level, affecting gene expression, protein interactions, etc.). </div><div class="MsoNormal"><br /></div><div class="MsoNormal">For a concrete property such as brain size, the amount of noise affecting the phenotype will be low, as a small number of components and processes are involved. The correspondence between genotype and phenotype will therefore be quite linear for concrete properties. In contrast, emergent properties that depend on large numbers of components will be more subject to noise and the relationship between genotype and phenotype will be far less linear.<span style="mso-spacerun: yes;">&nbsp; </span>This explains why mutations causing psychiatric disorders show lower <a href="http://en.wikipedia.org/wiki/Penetrance">penetrance</a> and higher variability in phenotypic expression – this is the predicted pattern for emergent properties. </div><div class="MsoNormal"><br /></div><div class="MsoNormal">To sum up, thinking about these kinds of disorders as affecting emergent properties can explain why they are common, why the genes responsible are so diverse, why their products are only distally and indirectly related to the processes affected by the clinical symptoms and why the phenotypic outcomes are inherently variable. </div></div>http://www.wiringthebrain.com/2013/03/the-genetics-of-emergent-phenotypes.htmlnoreply@blogger.com (Kevin Mitchell)22